KR20190006187A - Steroids as chemical intermediates 6.7. Beta.-Epoxide - Google Patents

Abstract

(Ia)The present invention relates to a process for the preparation of compounds of formula (Ia), wherein R ² , Y, R ⁴ and R ⁵ are as defined herein. The present invention also relates to certain compounds per se. The compounds are intermediates in the synthesis of synthetic bile acids.

(Ia)

Description

Steroids as chemical intermediates 6.7. Beta.-Epoxide

The present invention relates to a process for preparing a compound which is an intermediate in the synthesis of a bile acid derivative having pharmacological activity. In particular, the present invention relates to a process for the preparation of intermediates in the synthesis of obeticic acid and its analogs. The present invention further relates to novel intermediates per se.

Bile acids are steroidic acids found in the bile of mammals and include compounds such as cholic acid, chenodeoxycholic acid, lithocholic acid, and deoxycholic acid, all of which are found in humans. Many bile acids are natural ligands of the parnesoid X receptor (FXR) expressed in the liver and intestines of mammals, including humans.

Bile acids are derivatives of steroids and are numbered in the same way. The following formula shows the general numbering system for steroids and the numbering of the carbon atoms in the chenodeoxycholic acid.

      General steroid numbering CDCA numbering

FXR agonists have been shown to be useful in the treatment of cholestatic hepatic disorders including primary biliary cholangitis and non-alcoholic fatty liver disease (see Jonker et al. , Journal of Steroid Biochemistry & Molecular Biology , 2012 , 130 , 147-158).

Originally isolated from the gallbladder of bear, bile acid ursodeoxycholic acid (UDCA) is currently used for the treatment of cholestatic liver disorders, but it appears to be inactive in FXR.

In addition to their action in FXR, bile acids and their derivatives are also modulators of the G protein-coupled receptor TGR5. It is a member of the Rhodopsin-like superfamily of G-protein coupled receptors and plays an important role in the bile acid signaling network, which supplements the role of FXR.

Due to the importance of FXR and TGR5 agonists in the treatment of cholestatic liver disorders, efforts have been made to develop new compounds that exhibit agonist activity on these receptors. A particularly active primary compound is obeticol, which is a potent agonist of both FXR and TGR5. Obeticol acid is described in WO 02/072598 and EP 1568706 both of which are incorporated herein by reference and which are both processes for preparing obetic acid from 7-ketolitholic acid derived from cholic acid . Further processes for the preparation of obeticolanic acid and its derivatives are described in WO2006 / 122977, US2009 / 0062256, and WO2013 / 192097, both of which are incorporated herein by reference, All starting from 7-ketolytic acid.

It is clear from numerous patent publications on the process for the production of obeticic acid that it is not absolutely simple to synthesize these compounds and in fact the processes currently used start with cholic acid and have 12 steps and a low overall yield.

In addition to the inefficiency and high cost of this process, there is also a question of the price and availability of the raw materials. The current source for the production of obetic acid is colic acid, a natural bile acid that is commonly obtained from slaughter of cattle and other animals. This means that the availability of cholic acid and other bile acids is limited by the number of cattle available for slaughter. Since the incidence of cholestatic liver disease is increasing worldwide, there is a possibility that the demand for synthetic bile acids such as oveticol is also likely to increase and whether the supply of naturally induced bile acids will continue to be sufficient to meet demand It is uncertain.

In addition, the use of an animal-derived material may indicate contamination of the material with an infectious agent such as a virus or a prion, which may be hazardous to the operator, Potentially contaminate the final product.

Although some patients exhibiting cholestatic liver disease can be treated with ursodeoxycholic acid, they are also natural bile acids and face the same problems of limited availability and high cost.

In an attempt to solve the problem associated with the use of bile acid as a feedstock, the present inventors have found that synthetic bile acids such as ovitol cholic acid (OCA, referred to herein as compound (XA)), which uses plant sterol as a feedstock, A process for the synthesis of derivatives was devised.

Obeticolic acid (XA)

The inventors have developed a process for the preparation of synthetic bile acids which proceeds via novel intermediates and which provides the final products at significantly higher yields than the current process. The process is flexible and can use a variety of different materials including animal, fungal, and plant sterols.

Suitable animal sterols that can be used as a feedstock include deoxycholic acid, cholic acid, while fungal sterols include ergosterol.

Plant sterols are widely available at a significantly lower cost than bile acids and are often actually waste from other processes. Suitable plant sterols and plant sterol derivatives that may be used as a feedstock include, but are not limited to, bis-norcholenol (also known as 20-hydroxymethylpregn-4-en-3- one), androstenedione, androstadinedione, Dehydroepiandrosterone, stigmasterol, brassicasterol, campesterol, and beta-sitosterol.

The present inventors' patent applications No. PCT / GB2015 / 053516 (WO2016 / 079517), PCT / GB2015 / 053517 (WO2016 / 079518), PCT / GB2015 / 053518 (WO2016 / 079519) And PCT / GB2015 / 053519 (WO2016 / 079520), all of which are incorporated herein by reference, together with the intermediates in the synthesis of obethiolic acid (and analogs) To a process for switching.

The present application relates to additional compounds which are intermediates in the synthesis of obeticolanic acid and its analogs.

In one aspect of the present invention there is provided a compound of formula (Ia) or a salt or isotopic variant thereof:

(Ia)

(Ia)

In this formula,

R ² is H, halo, OH, or a protected OH group;

Y is a bond or a C _1-20 alkylene, C _2-20 alkenylene or C _2-20 alkynylene linker group, any of which is optionally substituted by one or more R ³ ;

Wherein each R ³ is independently H, halo, OH, protected OH group, or NR ⁸ R ⁹ ;

Wherein each R ⁸ and R ⁹ is independently H, C _1-6 alkyl, C (O) Ph, benzyl, phthalimide, tert -butyloxycarbonyl, or carboxybenzyl;

R ⁴ is ^{C (O) OR 10, OC} (O) R 10, C (O) NR 10 R 11, OR 10, OSi (R 13) 3, S (O) R 10, SO 2 R 10, OSO 2 _{^{R 10, SO 3 R 10,}} OSO 3 R 10, halo, CN, C (O) R 10, NR 10 R 11, BR 10 R 11, C (O) CH 2 N 2, -CH = CH 2, - C≡CH, CH [C (O) OR 10] 2, CH (BR 10 R 11) 2, ^{_{azide, NO 2, NR 10 C (}} O) NR 10 SO 2 R 11, NR 10 C (O) NR _{^{10 SO 2 NR 10 R 11,}} NR 10 SO 2 R 11, C (O) NR 10 SO 2 R 11, CH (XR 10) (XR 11), CH (R 10) (XR 11), phthalimide, Or a carboxylic acid mimetic group, such as a tetrazole;

Wherein each X is independently O, S, or NR ⁸ ;

Wherein each R < ¹⁰ > and R < ¹¹ >

a. Hydrogen;

b. C _1-6 alkyl, C _1-20 alkyl, C _3-7 cycloalkyl, C _2-20 alkenyl, or C _2-20 alkynyl,

C _1-4 alkyl, C _1-4 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, OSO ^{_{2 R 19, SO 3 R 19}} , OSO 3 R 19, N (R 19) 2, and 6-to 14-membered aryl or 5- to 14-membered heteroaryl group (each of which C _1-6 alkyl, C thereof _1-6 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO 3 R 19, and N ( R < ¹⁹ >)₂; or a pharmaceutically acceptable salt thereof;

c. 6- to 14-membered aryl, 5- to 14-membered heteroaryl group, or 3- to 10-membered heterocyclic ring, any of which is

(O) C _1-4 alkyl, SR ¹⁹ , C (O) C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, halo, NO ₂ , CN, OR ¹⁹ , ^{) OR 19, C (O)} N (R 19) 2, SO 2 R 19, SO 3 R 19, N (R 19) 2, Phenyl, 5- to 14-membered heteroaryl, 3- to 10-membered heterocyclic ring, methylenedioxy, and ethylene dioxy;

d. A polyethylene glycol residue;

e. R ⁴ is ^{C (O) NR 10 R 11} , CH (XR 10) (XR 11), CH (R 10) (XR 11), NR 10 R 11, BR 10 R 11, CH [C (O) OR 10 ] ₂ , or CH (BR ¹⁰ R ¹¹ ) ₂ , the R ¹⁰ and R ¹¹ groups may be combined with the atoms or atoms to which they are attached to form a 3- to 10-membered heterocyclic ring;

Wherein each R < ¹⁹ > is independently

H, C _1-6 alkyl, C _1-6 haloalkyl, or a 6- to 14-membered aryl or 5- to 14-membered heteroaryl group, each of which is halo, C _1-6 alkyl, and C _{1- 6} haloalkyl; < / RTI >

Wherein each R < ¹³ > is independently

a. C _1-20 alkyl, C _2-20 alkenyl or C _2-20 alkynyl, any of which is

^{_{Halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO 3 R 19, OSO 3 R 19, N (R 19 ) _2, and 6-to 14-membered aryl or 5- to 14-membered heteroaryl group (each of which C _1-6 alkyl, C _1-6 haloalkyl, halo, NO _2, CN, oR ^19, SO ₂ Optionally substituted by one or more substituents selected from R ¹⁹ , SO ₃ R ¹⁹ , and N (R ¹⁹ ) ₂ ;

b. 6- to 14-membered aryl or 5- to 14-membered heteroaryl group,

C _1-6 alkyl, C _1-6 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO ₃ R ^19, and N (R ¹⁹⁾ _2, and optionally substituted by one or more substituents selected from;

Wherein each R < ¹⁹ > is independently

H, Ci- ₆ alkyl, or Ci- ₆ haloalkyl;

Y and R ⁴ together form a group = CH _2;

R ⁵ is H, OH, or a protected OH group.

In another aspect of the present invention there is provided a compound of formula (I) or a salt or isotopic variant thereof:

(I)

(I)

In this formula,

R ² is H, halo, OH, or a protected OH group;

Y is a bond or a C _1-20 alkylene, C _2-20 alkenylene or C _2-20 alkynylene linker group, any of which is optionally substituted by one or more R ³ ;

Wherein each R ³ is independently halo, OR ⁸ , or NR ⁸ R ⁹ ;

Wherein each R ⁸ and R ⁹ is independently H or C _1-4 alkyl;

R ⁴ is ^{C (O) OR 10, OC} (O) R 10, C (O) NR 10 R 11, OR 10, OSi (R 13) 3, S (O) R 10, SO 2 R 10, OSO 2 _{^{R 10, SO 3 R 10,}} OSO 3 R 10, halo, CN, C (O) R 10, CH (OR 10) (OR 11), CH (R 10) (OR 11), CH (SR 10) ( ^{SR 11), NR 10 R 11} , BR 10 R 11, C (O) CH 2 N 2, -CH = CH 2, -C≡CH, CH [C (O) OR 10] 2, CH (BR 10 R ¹¹ ) ₂ , an azide, or a carboxylic acid analog, such as a tetrazole;

Wherein each R < ¹⁰ > and R < ¹¹ >

a. Hydrogen;

b. C _1-20 alkyl, C _2-20 alkenyl or C _2-20 alkynyl, any of which is

^{_{Halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO 3 R 19, OSO 3 R 19, N (R 19 ) _2, and 6-to 14-membered aryl or 5- to 14-membered heteroaryl group (each of which C _1-6 alkyl, C _1-6 haloalkyl, halo, NO _2, CN, oR ^19, SR ¹⁹ selected ^{from, C (O) OR 19,} C (O) N (R 19) 2, SO 2 R 19, SO 3 R 19, and N (R ^19), optionally substituted by one or more substituents selected from ₂₎ Lt; / RTI > is optionally substituted by one or more substituents;

c. 6- to 14-membered aryl or 5- to 14-membered heteroaryl group,

C _1-6 alkyl, C _1-6 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO ₃ R ^19, and N (R ¹⁹⁾ ₂ with one or more substituents selected from optionally substituted;

d. A polyethylene glycol residue;

e. R ⁴ is ^{C (O) NR 10 R 11} , CH (OR 10) (OR 11), CH (R 10) (OR 11), CH (SR 10) (SR 11), NR 10 R 11, BR 10 R ^{11, CH [C (O)} oR 10] 2, or CH (BR ¹⁰ R ¹¹⁾ ₂ in the case of R ¹⁰ and R ¹¹ group is combined with the atom or atoms to which they are attached, a 3- to 10-membered heteroaryl To form a cyclic ring;

Wherein each R < ¹⁹ > is independently

H, C _1-6 alkyl, C _1-6 haloalkyl, or a 6- to 14-membered aryl or 5- to 14-membered heteroaryl group, each of which is halo, C _1-6 alkyl, and C _{1- 6} haloalkyl; < / RTI >

Wherein each R < ¹³ > is independently

a. C _1-20 alkyl, C _2-20 alkenyl or C _2-20 alkynyl, any of which is

^{_{Halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO 3 R 19, OSO 3 R 19, N (R 19 ) _2, and 6-to 14-membered aryl or 5- to 14-membered heteroaryl group (each of which C _1-6 alkyl, C _1-6 haloalkyl, halo, NO _2, CN, oR ^19, SO ₂ Optionally substituted by one or more substituents selected from R ¹⁹ , SO ₃ R ¹⁹ , and N (R ¹⁹ ) ₂ ;

b. 6- to 14-membered aryl or 5- to 14-membered heteroaryl group,

C _1-6 alkyl, C _1-6 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO ₃ R ^19, and N (R ¹⁹⁾ _2, and optionally substituted by one or more substituents selected from;

Wherein each R < ¹⁹ > is independently

H, Ci- ₆ alkyl, or Ci- ₆ haloalkyl;

Y and R ⁴ together form a group = CH _2;

R ⁵ is H, OH, or a protected OH group.

Compounds of general formula (Ia) and (I) are useful as intermediates in the synthesis of obetic acid and its analogs.

Another aspect of the present invention provides a process for preparing a compound of formula (Ia), comprising reacting a compound of formula (IIa) with a halogenating agent followed by reaction with a base to provide a compound of formula (Ia) A process is provided:

               (IIa)    (Ia)

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

In another aspect of the present invention, there is provided a process for the preparation of compounds of formula (II) in which TCCA, TIBA, TICA, , Dimethylhydantoin (DCDMH), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), or 1,3-diiodo-5,5-dimethylhydantoin (DIDMH) To give a compound of general formula (I) by reaction with a base followed by reaction with a base to give a compound of general formula (I)

                (II)     (I)

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (I).

In another aspect of the present invention there is provided a process for preparing a compound of formula (Ia), comprising the steps of:

(A) Reacting a compound of formula (IIa) with a halogenating agent to provide a compound of formula (IIIxa) and / or a compound of formula (IIIya)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for a compound of formula (Ia)

And

(B) Reacting a compound of formula (IIIxa) and / or a compound of formula (IIIya) with a base to form a compound of formula (Ia)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for a compound of formula (Ia).

In another aspect of the present invention there is provided a process for preparing a compound of general formula (I), comprising the steps of:

(A) Compounds of formula (II) can be prepared by reacting compounds of formula (II) with trichloroisocyanuric acid (TCCA), tribromoisocyanuric acid (TBCA), triiodoisothiocyanuric acid (TICA), 1,3-dichloro-5,5-dimethylhydantoin Dibromo-5,5-dimethylhydantoin (DBDMH), or 1,3-diiodo-5,5-dimethylhydantoin (DIDMH) ≪ / RTI > and / or a compound of formula (IIIy)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for a compound of formula (I)

And

(B) Reacting a compound of formula (IIIx) and / or a compound of formula (IIIy) with a base to form a compound of formula (I)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for a compound of formula (I).

In a further aspect of the present invention there is provided a compound of formula (IIIxa) and formula (IIIya), and a compound of formula (IIIx) and formula (IIIy) Lt; RTI ID = 0.0 > (I) < / RTI >

Accordingly, one aspect of the present invention provides a compound of formula (IIIxa), or a salt or isotopic variant thereof:

(IIIxa)

(IIIxa)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

In one aspect of the present invention, there is provided a compound of formula (IIIx) or a salt or isotopic variant thereof:

(IIIx)

(IIIx)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (I).

In another aspect of the present invention there is provided a compound of formula (IIIya), or a salt or isotopic variant thereof:

(IIIya)

(IIIya)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

In another aspect of the present invention there is provided a compound of formula (IIIy) or a salt or isotopic variant thereof:

(IIIy)

(IIIy)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (I).

In one embodiment, a mixture of a compound of formula (IIIxa) and a compound of formula (IIIya) is provided. In one embodiment, a mixture of a compound of formula (IIIx) and a compound of formula (IIIy) is provided.

In one embodiment, there is provided a mixture comprising a compound of formula (IIIxa) and a compound of formula (IIIya). In one embodiment, there is provided a mixture comprising a compound of formula (IIIx) and a compound of formula (IIIy).

In another aspect of the present invention there is provided a process for preparing a compound of formula (Ia), comprising the steps of:

(A) The compound of formula (IIa) is reacted with a halogenating agent to obtain a compound of formula (IIIxa) and / or a compound of formula (IIIya) and / or a compound of formula (IIIxz) and / Providing:

Wherein X is Cl, Br, or I;

R ⁴⁰ is C (O) H, C (O) C _1-4 alkyl, C (O) phenyl, C (O) benzyl, phenyl, benzyl, C _2-4 alkenyl or SO ₂ CF ₃ ; Here, in C (O) -phenyl, C (O) benzyl, phenyl, and benzyl is C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI > is optionally substituted by one or more substituents selected;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for a compound of formula (Ia)

And

(B) The compound of formula (Ia) may be prepared by reacting a compound of formula (IIIxa) and / or a compound of formula (IIIxa) and / or a compound of formula (IIIxz) and / Forming step:

Wherein X is Cl, Br, or I;

R ⁴⁰ is C (O) H, C (O) C _1-4 alkyl, C (O) phenyl, C (O) benzyl, phenyl, benzyl, C _2-4 alkenyl or SO ₂ CF ₃ ; Here, in C (O) -phenyl, C (O) benzyl, phenyl, and benzyl is C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI > is optionally substituted by one or more substituents selected;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for a compound of formula (Ia).

In this embodiment, suitably, step (A) is carried out in the presence of HOC (O) R ^x , HOR ^y , or HSO ₃ R ^z ; Wherein R ^x is H, C _1-4 alkyl (e.g., methyl or ethyl), phenyl or benzyl; R ^y is phenyl, benzyl, or C _2-4 alkene (e.g., allyl); R ^z is CF ₃ wherein phenyl and benzyl are optionally substituted with one or more substituents selected from C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI > HOR ^x , HOR ^y , or HSO ₃ R ^z can be present as an additive in the reaction (suitably in the absence of water and in the presence of an aprotic solvent) or as the reaction solvent itself.

In this aspect of the present invention, a mixture of a compound of formula (IIIxa) and / or a compound of formula (IIIya) and / or a compound of formula (IIIxz) and / Lt; RTI ID = 0.0 > B < / RTI >

In one embodiment, the process further comprises removing the group R < RTI ID = 0.0 > ⁴⁰ < / RTI > In one embodiment, the process further comprises the step of removing group R ⁴⁰ prior to performing step (B).

In one aspect of the present invention there is provided a compound of formula (IIIxz), or a salt or isotopic variant thereof:

(IIIxz)

(IIIxz)

Wherein X is Cl, Br, or I;

R ⁴⁰ is C (O) H, C (O) C _1-4 alkyl, C (O) phenyl, C (O) benzyl, phenyl, benzyl, C _2-4 alkenyl or SO ₂ CF ₃ ; Here, in C (O) -phenyl, C (O) benzyl, phenyl, and benzyl is C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI > is optionally substituted by one or more substituents selected;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

In another aspect of the present invention there is provided a compound of formula (IIIyz) or a salt or isotopic variant thereof:

(IIIyz)

(IIIyz)

Wherein X is Cl, Br, or I;

R ⁴⁰ is C (O) H, C (O) C _1-4 alkyl, C (O) phenyl, C (O) benzyl, phenyl, benzyl, C _2-4 alkenyl or SO ₂ CF ₃ ; Here, in C (O) -phenyl, C (O) benzyl, phenyl, and benzyl is C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI > is optionally substituted by one or more substituents selected;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

In one embodiment, there is provided a mixture comprising a compound of formula (IIIxz) and a compound of formula (IIIyz).

Compounds of general formula (Ia) and (I) are useful in the synthesis of obetic acid and its analogs.

The compounds of formula (Ia) are useful for the preparation of compounds of formula (Xa) or salts or isotopic variations thereof:

(Xa)

(Xa)

In this formula,

R ¹ is C _1-4 alkyl, C _2-4 alkenyl, or C _2-4 alkynyl optionally substituted by one or more substituents selected from halo, OR ⁶ , and NR ⁶ R ⁷ ;

Wherein each R ⁶ and R ⁷ is independently H or C _1-4 alkyl;

R ² is H, halo, or OH;

Y ¹ is a bond or a C _1-20 alkylene linker group optionally substituted by one or more R ³ ;

Y ¹ and R ⁴ together form a = CH ₂ group;

R < ^5a > is H or OH;

Wherein R < ³ > and R < ⁴ > are as described above for the compound of formula (Ia).

The compounds of formula (I) are useful for the preparation of compounds of formula (X) or salts or isotopic variations thereof:

(X)

(X)

In this formula,

R ¹ is C _1-4 alkyl optionally substituted by one or more substituents selected from halo, OR ⁶ , and NR ⁶ R ⁷ ;

Wherein each R ⁶ and R ⁷ is independently H or C _1-4 alkyl;

R ² is H, halo, or OH;

Y ¹ is a bond or a C _1-20 alkylene linker group optionally substituted by one or more R ³ ;

Y ¹ and R ⁴ together form a = CH ₂ group;

R < ^5a > is H or OH;

Wherein R < ³ > and R < ⁴ > are as described above for the compound of formula (I).

In one aspect of the present invention there is provided a process for the preparation of a compound of formula (Ia), (IVa), (Va), (Va) There is provided a process for preparing a compound of formula (Xa) from a compound of formula (Ia) further comprising at least one optional step of converting a compound of formula (Xa), (VIa)

(a) Optionally alkylating the compound of formula (Ia) with an organometallic reagent to provide a compound of formula (IVa)

(IVa)

(IVa)

Wherein R < ¹ > is as defined for a compound of formula (Xa);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia);

(b) Reduction of the compound of formula (IVa) using a suitable reducing agent to provide the compound of formula (Va)

(Va)

(Va)

(Wherein, R ¹ and Y ¹ are as defined for a compound of formula (Xa);

R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia);

(c) Oxidizing the compound of formula (Va) using a suitable oxidizing agent to provide a compound of formula (VIa)

(VIa)

(VIa)

(Wherein, R ¹ and Y ¹ are as defined for a compound of formula (Xa);

R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia);

(d) reducing the compound of formula (VIa) using a suitable reducing agent and removing the protecting group (s) when R ² and / or R ⁵ is protected OH, Wherein removal of the protecting group may take place before or after reduction.

Any stage following general formula (Ia), (IVa), (Va), (VIa), by reacting a compound side chain of and (Xa) alternative Y and / or R ⁴ compound with a moiety as described As shown in FIG.

In one aspect of the present invention there is provided a process for the preparation of a compound of formula (I), (IV), (V), (V) There is provided a process for preparing a compound of formula (X) from a compound of formula (I) further comprising at least one optional step of converting a compound of formula (I), (VI)

(a) Optionally alkylating the compound of formula (I) with an organometallic reagent to provide a compound of formula (IV)

(IV)

(IV)

Wherein R < ¹ > is as defined for a compound of formula (X);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (I);

(b) Reduction of the compound of formula (IV) using a suitable reducing agent to provide the compound of formula (V)

(V)

(V)

(Wherein, R ¹ and Y ¹ are as defined for a compound of formula (X);

R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (I);

(c) Oxidizing the compound of formula (V) using a suitable oxidizing agent to provide the compound of formula (VI)

(VI)

(VI)

(Wherein, R ¹ and Y ¹ are as defined for a compound of formula (X);

R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (I);

(d) reducing the compound of formula (VI) using a suitable reducing agent and removing the protecting group (s) when R ² and / or R ⁵ is protected OH, Wherein removal of the protecting group may take place before or after reduction.

Any stage following general formula (I), (IV), (V), (VI), and reacting the side chain of the compound of (X) alternate Y and / or R ⁴ compound with a moiety as described As shown in FIG.

A further aspect of the present invention provides a compound of formula (IVa) and a compound of formula (Va) per se, and a compound of formula (IV) and a compound of formula (V) Are useful as intermediates in the synthesis of compounds of formula (Xa) and compounds of formula (X), respectively.

Accordingly, one aspect of the present invention provides a compound of formula (IVa), or a salt or isotopic variant thereof:

(IVa)

(IVa)

Wherein R ¹ is as defined for a compound of formula (Xa);

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia).

In one aspect of the present invention there is provided a compound of formula (IV) or a salt or isotopic variant thereof:

(IV)

(IV)

Wherein R < ¹ > is as defined for a compound of formula (X);

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (I).

In another aspect of the present invention there is provided a compound of formula (Va) or a salt or isotopic variant thereof:

(Va)

(Va)

Wherein R, R ¹ and Y ¹ are as defined for a compound of formula (Xa);

R ² , R ⁴ , and R ⁵ are as defined for compounds of formula (Ia).

In another aspect of the present invention there is provided a compound of formula (V) or a salt or isotopic variant thereof:

(V)

(V)

Wherein R ¹ and Y ¹ are as defined for a compound of formula (X);

R ² , R ⁴ , and R ⁵ are as defined for compounds of formula (I).

1 shows a representative conversion of the compounds of formula (IIa) or of formula (II) in which the side chain is -CH ₂ OH to the other compounds of formula (IIa) or of formula (II), respectively with different side chains .
2 shows the ¹ H NMR spectrum of (6β, 7α, 22E) -6-acetoxy-7-chloro-3-oxo-4,22-colladiene-24-oic acid ethyl ester (see Example 2).
Figure 3 shows the ¹³ C NMR spectrum of (6β, 7α, 22E) -6-acetoxy-7-chloro-3-oxo-4,22-colladiene-24-oic acid ethyl ester (see Example 2).
Figure 4: (22 E) -6,7- epoxy-3-oxo -4,22- coke diene -24- of miscalculation ethyl ester (6β, 7β) and (6α, 7α) 2 isomers: 1 mixture of the ¹ ≪ 1 > H NMR (see Example 4).
Figure 5: (6α, 7α, 22 E) -6,7- epoxy-3-oxo -4,22- coke diene -24- Osan ethyl ester (Alfa) and (6β, 7β, 22 E) -6,7 -epoxy-3-oxo -4,22- prepared from coke diene -24- Osan ethyl ester (beta) (5β, 6α) -3,7- ^{dioxo-6-ethyl-1} H kolran -24- miscalculation of NMR < / RTI >
Figure 6: (6α, 7α, 22 E) -6,7- epoxy-3-oxo -4,22- coke diene -24- Osan ethyl ester (Alfa) and (6β, 7β, 22 E) -6,7 -epoxy-3-oxo -4,22- coke diene -24- Osan ethyl ester prepared from (beta) (5β, 6α) -3,7- ^{dioxo-6-ethyl-13} C for kolran -24- Osan NMR < / RTI >

Variations such as the word " comprise ", or " comprise ", or " comprise ", in this specification are intended to be inclusive in a generic sense, But is used in various embodiments of the invention to specify the presence of stated features, not to preclude the presence or addition of additional features.

All publications, including but not limited to the patents and patent applications listed in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as if fully set forth .

The term " C _1-20 " alkyl as used herein refers to a fully saturated straight or branched hydrocarbon group having from 1 to 20 carbon atoms. The term includes methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, s -butyl, and t -butyl. Other alkyl groups such as C _1-12 alkyl, C _1-10 alkyl, C _1-8 alkyl, C _1-6 alkyl, C _1-5 alkyl, C _1-4 alkyl, C _1-3 alkyl, or C _1-2 alkyl is as defined above but contains a different number of carbon atoms.

The terms " heterocyclic " and " heterocyclyl " are intended to include those having from 3 to 10 ring atoms and at least one heteroatom selected from N, O, S, and B, optionally substituted by one or more = O moieties Refers to a non-aromatic cyclic group. Examples of heterocyclic groups include pyrrolidine, piperidine, morpholine, piperazine, tetrahydrofuran, dioxolane (e.g., 1,3-dioxolane), dioxane Oxane), and cyclic thioethers. The term also includes non-cyclic and bridged groups such as 9-borabicyclo (3.3.1) nonane (9-BBN).

The term " halogen " refers to fluorine, chlorine, bromine, or iodine, and the term " halo " refers to a fluoro, chloro, bromo, or iodo group.

The term "C _1-6 haloalkyl" refers to an linear or branched alkyl, such as up to perhalo by one or more halo atoms numbered 1 to 6 carbon atoms as defined above which is substituted by substituted. Examples include trifluoromethyl, chloroethyl, and 1,1-difluoroethyl. Other haloalkyl groups such as C _1-5 haloalkyl, C _1-4 haloalkyl, C _1-3 haloalkyl, or C _1-2 haloalkyl are as defined above but contain a different number of carbon atoms .

The term " C _2-20 alkenyl " refers to a straight or branched hydrocarbon group having from 2 to 20 carbon atoms and at least one carbon-carbon double bond. Examples include ethenyl (vinyl), prop-1-enyl, prop-2-enyl (allyl), hex-2-enyl and the like. Other alkenyl groups such as C _2-12 alkenyl, C _2-10 alkenyl, C _2-8 alkenyl, C _2-6 alkenyl, C _2-5 alkenyl, C _2-4 alkenyl, Or C _2-3 alkenyl are as defined above but contain a different number of carbon atoms.

The term " C _2-20 alkynyl " refers to a straight or branched hydrocarbon group having from 2 to 20 carbon atoms and at least one carbon-carbon triple bond. Examples include ethynyl, prop-1-ynyl, hex-2-ynyl, and the like. Other alkynyl groups such as C _2-12 alkynyl, C _2-10 alkynyl, C _2-8 alkynyl, C _2-6 alkynyl, C _2-5 alkynyl, C _2-4 alkynyl, Or C _2-3 alkynyl are as defined above but contain a different number of carbon atoms.

The term " alkylene " refers to a fully saturated linear or branched hydrocarbon chain. Suitably the alkylene is C _1-20 alkylene, C _1-12 alkylene, C _1-10 alkylene, C _1-8 alkylene, C _1-6 alkylene, C _1-5 alkylene, C _{1- 4} alkylene, C _1-3 alkylene is alkylene, or C _1-2 alkyl. Examples of alkylene groups include _{-CH 2 -, -CH 2 CH 2} -, -CH (CH 3) -CH 2 -, -CH 2 CH (CH 3) -, -CH 2 CH 2 CH 2 -, -CH ₂ CH (CH ₂ CH ₃ ) -, and -CH ₂ CH (CH ₂ CH ₃ ) CH ₂ -.

The term " alkenylene " refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Suitably alkenylene is C _2-20 alkenylene, C _2-12 alkenylene, C _2-10 alkenylene, C _2-8 alkenylene, C _2-6 alkenylene, C _2-5 alkenylene, C _{2- 4} alkenylene, or C _2-3 alkenylene. Examples of alkenylene groups include -CH = CH-, -CH = C ( CH 3) -, -CH 2 CH = CH-, -CH = CHCH 2 -, -CH 2 CH 2 CH = CH-, -CH 2 CH = C (CH ₃₎ - comprises -, and _{-CH 2 CH = C (CH 2} CH 3).

The term " C _2-20 alkynyl " refers to a straight or branched hydrocarbon group having from 2 to 20 carbon atoms and at least one carbon-carbon triple bond. Examples include ethynyl, prop-1-ynyl, hex-2-ynyl, and the like. Other alkynyl groups such as C _2-12 alkynyl, C _2-10 alkynyl, C _2-8 alkynyl, C _2-6 alkynyl, C _2-5 alkynyl, C _2-4 alkynyl, Or C _2-3 alkynyl are as defined above but contain a different number of carbon atoms.

The term " alkyl " refers to a fully saturated linear or branched hydrocarbon chain. Suitably the alkylene is C _1-20 alkyl, C _1-12 alkyl, C _1-10 alkyl, C _1-8 alkyl, C _1-6 alkyl, C _1-5 alkyl, C _1-4 alkyl, C _{1- 3} alkyl, or C < _1-2 > alkyl. Examples of alkyl groups include _{-CH 3, -CH 2 CH 3,} -CH (CH 3) -CH 3, -CH 2 CH 2 CH 3, -C (CH 3) 3, and -CH ₂ CH ₂ CH ₂ CH ₃ .

The term " alkenyl " refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Suitably the alkenyl is C _2-20 alkenyl, C _2-12 Al, C _2-10 alkenyl, C _2-8 alkenyl, C _2-6 alkenyl, C _2-5 alkenyl, C _{2- 4} alkenyl, or C _2-3 alkenyl. Examples of groups alkenyl is _{-CH = CH 2, -CH = CH} (CH 3), -CH 2 CH = CH 2, -CH = CHCH 3, -CH 2 CH 2 CH = CH 2, -CH 2 CH = CH (CH ₃₎ -, and a _{-CH 2 CH = CH (CH 2} CH 3).

The term " alkynylene " refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Suitably alkynylene is C _2-20 alkynylene, C _2-12 alkynylene, C _2-10 alkynylene, C _2-8 alkynylene, C _2-6 alkynylene, C _2-5 alkynylene, C _{2- 4} alkynylene, or C _2-3 alkynylene. Examples of alkynylene groups are -C≡C-, -CH ₂ C≡C-, -C≡C-CH ₂ -, -CH ₂ CH ₂ C≡C-, -CH ₂ C≡CCH ₂ -, and - CH ₂ C≡C-CH ₂ CH ₂ -.

The term " aryl " and " aromatic " refers to a cyclic group having an aromatic character that contains up to three rings, with 6 to 14 ring carbon atoms (for example, 6 to 10 ring carbon atoms unless otherwise specified) . When an aryl group contains more than one ring, not all rings need to be aromatic. Examples include partially saturated systems such as phenyl, naphthyl, and anthracenyl, such as tetrahydronaphthyl, indanyl, and indenyl. A further example of an aryl group is 1,2,3,4-tetrahydronaphthalene.

The term " heteroaryl " and " heteroaromatic " refers to heteroaromatic rings having 5 to 14 ring atoms (for example, 5 to 10 ring atoms unless otherwise specified), at least one of which is heteroatom selected from N, O, Quot; refers to a cyclic group having an aromatic character and containing up to three rings. When the heteroaryl group contains more than one ring, not all rings need be aromatic. Examples of heteroaryl groups include pyridine, pyrimidine, indole, benzofuran, benzimidazole, and indolene. Further examples of heteroaryl groups include quinolines and isoquinolines.

The term " isotopic variant " refers to an atom or mass representing an atomic mass or number of masses that are replaced with one or more atoms by atoms representing the atomic mass or mass number different from the atomic mass or mass number most commonly found in nature, Refers to the same isotopically-labeled compounds as those listed in formula (Ia) or formula (I) unless the ratio of the isotope enrichment is increased (the latter concept is referred to as "isotope enrichment"). Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, such as ² H (deuterium), ³ H, ¹¹ C, ¹³ C, ¹⁴ C , ¹⁸ F, ¹²³ I, or ¹²⁵ I (such as ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ¹²³ I, or ¹²⁵ I), which may be naturally occurring or non- .

Polyethylene glycol (PEG) is a polyether compound which has the general formula H- [O-CH ₂ -CH ₂ ] _n -OH in linear form. The polyethylene glycol moiety is a PEG in which the terminal H is replaced by a bond linking it to the rest of the molecule.

Bifurcated versions, including hyperbranched and dendritic versions, are also contemplated and are generally known in the art. Typically, the branched polymer has a central branch core moiety and a plurality of linear polymer chains connected to the central branch core. PEG is typically used in branched form, which can be prepared by adding ethylene oxide to various polyols such as glycerol, glycerol oligomer, pentaerythritol, and sorbitol. The central branching moiety may also be derived from some amino acids, such as lysine. Branched poly (ethylene glycol) can be represented in general form as R (-PEG-OH) _m , where R is derived from a core moiety such as glycerol, glycerol oligomer, or pentaerythritol, arm. Multi-arm PEG molecules such as those described in US 5,932, 462; US 5,643,575; US 5,229,490; US 4,289, 872; US2003 / 0143596; WO96 / 21469; And WO93 / 21259, all of which are incorporated herein by reference, may also be used.

The PEG polymer may be, for example, 600-2,000,000 Da, 60,000-2,000,000 Da, 40,000-2,000,000 Da, 400,000-1,600,000 Da, 800-1,200,000 Da, 600-40,000 Da, 600-20,000 Da, 4,000-16,000 Da, -12,000 Da. ≪ / RTI >

The term " protected OH " refers to an OH group protected by any suitable protecting group. For example, the protected OH may be a group R < ⁴ >, as defined above.

Suitable protecting groups include, for example, R ² and / or R ⁵ and / or R ³ in this case a protected OH group, R ² and / or R ⁵ and / or R ³ is independently a group OC (O) R ¹⁴ may be Wherein R < ¹⁴ > includes an ester group R < ¹⁰ > as defined above. In this case, R ² and / or R ⁵ and / or R ³ may independently be a group OSi (R ¹⁶ ) ₃ , wherein each R ¹⁶ is independently selected from the group consisting of is a group R ^13.

Other suitable protecting groups for OH are well known to those skilled in the art (a document incorporated herein by reference [Wuts, PGM and Greene, TW (2006) "Greene's Protective Groups in Organic Synthesis", 4 th Edition, John Wiley & Sons , Inc., Hoboken, NJ, USA).

Salts of the compounds of formula (XVIIIa) and (XVIII) are suitably pharmaceutical or veterinarily acceptable salts. Salts that are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.

Reference to a stable protecting group under basic conditions means that the protecting group can not be removed by treatment with a base.

Suitable salts of the compounds described herein are described in Paulekuhn et al., J. Med . Chem. 2007, 50, 6665-6672], and are summarized in (incorporated by reference herein) and / or, base addition salts, such as sodium, potassium, calcium, aluminum, zinc, magnesium, and other metal salts as well known to those skilled in the art And choline, diethanolamine, ethanolamine, ethylenediamine, meglumine, and other common base addition salts.

The term "carboxylic acid group similar" is well-known, including tetrazole, substituted ^{_{tetrazoles, -SO 2 -NHR 10, C (}} O) NH-SO 2 R 10, and _{NHC (O) NH-SO 2} R 10 Lt; RTI ID = 0.0 > of: < / RTI >

Wherein R ¹⁰ is as defined above for a compound of formula (Ia) or (I) and is suitably H, C _1-6 alkyl, C _3-7 cycloalkyl, or 6- to 14-membered aryl For example phenyl).

The tetrazole group includes tetrazol-5-yl and tetrazol-1-yl. Substituted tetrazole are C _1-4 alkyl, halo, OH, O (C _1-4 alkyl), or SO ₂ R ¹⁰ (e.g. SO ₂ (C _1-4 alkyl), SO ₂ -, phenyl, or SO ₂ -tolyl). ≪ / RTI >

Such carboxylic acid analogs are well known in the art and include, for example, " On Medicinal Chemistry "; M Stocks, L Alcaraz, E Griffen; Pub: Sci-ink Ltd (April 2007)].

Particularly suitable acid groups are similar to tetrazole, comprising a _{C (O) NH-SO 2} R 10, and _{NHC (O) NH-SO 2} R 10, tetrazole are particularly preferable.

In one aspect of the invention, there is provided a compound of formula (Ia)

(Ia)

(Ia)

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above.

Suitably the compound of formula (Ia) is < RTI ID = 0.0 >

(Ia)

(Ia)

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above.

In one embodiment, the compound of formula (Ia)

이다.

to be.

In one embodiment, the compound of formula (Ia)

이다.

to be.

In one embodiment, the compound of formula (Ia)

가 아니다.

.

In one embodiment, the compound of formula (Ia)

가 아니다.

.

In one aspect of the invention, there is provided a compound of formula (I)

(I)

(I)

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above.

Suitably, the compounds of formula (I) are the following compounds:

(I)

(I)

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above.

In one embodiment, the compound of formula (I)

가 아니다.

.

In one embodiment, the compound of formula (I)

가 아니다.

.

In another aspect of the present invention there is provided a compound of formula (IIIxa) or a salt or isotopic variant thereof:

(IIIxa)

(IIIxa)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

Suitably, the compound of formula (IIIxa) is the following compound or salt or isotopic variant thereof:

(IIIxa)

(IIIxa)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

In another aspect of the present invention there is provided a compound of formula (IIIx), or a salt or isotopic variant thereof:

(IIIx)

(IIIx)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (I).

Suitably, the compounds of formula (IIIIx) are the following compounds or salts or isotopic variations thereof:

(IIIx)

(IIIx)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (I).

In another aspect of the present invention there is provided a compound of formula (IIIya), or a salt or isotopic variant thereof:

(IIIya)

(IIIya)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

Suitably, the compound of formula (IIIya) is the following compound or salt or isotopic variant thereof:

(IIIya)

(IIIya)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

In another aspect of the present invention there is provided a compound of formula (IIIy) or a salt or isotopic variant thereof:

(IIIy)

(IIIy)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (I).

Suitably, the compound of formula (IIIy) is the following compound or salt or isotopic variant thereof:

(IIIy)

(IIIy)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (I).

In a further aspect of the present invention there is provided a compound of formula (IVa) or a salt or isotopic variant thereof:

(IVa)

(IVa)

Wherein R < ¹ > is as defined for a compound of formula (Xa);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia).

Suitably the compound of formula (IVa) is the following compound or salt or isotopic variant thereof:

(IVa)

(IVa)

Wherein R < ¹ > is as defined for a compound of formula (Xa);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia).

Suitably the compound of formula (IVa) is the following compound or salt or isotopic variant thereof:

(IVa)

(IVa)

Wherein R < ¹ > is as defined for a compound of formula (Xa);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia).

Suitably the compound of formula (IVa) is the following compound or salt or isotopic variant thereof:

(IVa)

(IVa)

Wherein R < ¹ > is as defined for a compound of formula (Xa);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia).

In a further aspect of the present invention there is provided a compound of formula (IV) or a salt or isotopic variant thereof:

(IV)

(IV)

Wherein R < ¹ > is as defined for a compound of formula (X);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of general formula (I).

Suitably the compound of formula (IV) is the following compound or salt or isotopic variant thereof:

(IV)

(IV)

Wherein R < ¹ > is as defined for a compound of formula (X);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of general formula (I).

Suitably the compound of formula (IV) is the following compound or salt or isotopic variant thereof:

(IV)

(IV)

Wherein R < ¹ > is as defined for a compound of formula (X);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of general formula (I).

Suitably the compound of formula (IV) is the following compound or salt or isotopic variant thereof:

(IV)

(IV)

Wherein R < ¹ > is as defined for a compound of formula (Xa);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of general formula (I).

In a further aspect of the present invention there is provided a compound of formula (Va) or a salt or isotopic variant thereof:

(Va)

(Va)

Wherein Y ¹ and R ¹ are as defined above for a compound of formula (Xa);

R ² , R ⁴ , and R ⁵ are as defined for compounds of formula (Ia).

In a further aspect of the invention there is provided a compound of formula (V) or a salt or isotopic variant thereof:

(V)

(V)

Wherein Y ¹ and R ¹ are as defined above for a compound of formula (X);

R ² , R ⁴ , and R ⁵ are as defined for compounds of formula (I).

In one aspect of the present invention there is provided a compound of formula (IIIxz), or a salt or isotopic variant thereof:

(IIIxz)

(IIIxz)

Wherein X is Cl, Br, or I;

Wherein R ⁴⁰ is C (O) H, C (O) C _1-4 alkyl, C (O) phenyl, C (O) benzyl, phenyl, benzyl, C _2-4 alkenyl, or SO ₂ CF ₃ ; Here, in C (O) -phenyl, C (O) benzyl, phenyl, and benzyl is C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI > is optionally substituted by one or more substituents selected; Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

Suitably, the compound of formula (IIIIxz) is the following compound or salt or isotopic variant thereof:

(IIIxz)

(IIIxz)

Wherein X is Cl, Br, or I;

Wherein R ⁴⁰ is C (O) H, C (O) C _1-4 alkyl, C (O) phenyl, C (O) benzyl, phenyl, benzyl, C _2-4 alkenyl, or SO ₂ CF ₃ ; Here, in C (O) -phenyl, C (O) benzyl, phenyl, and benzyl is C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI > is optionally substituted by one or more substituents selected; Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

In another aspect of the present invention there is provided a compound of formula (IIIyz) or a salt or isotopic variant thereof:

(IIIyz)

(IIIyz)

Wherein X is Cl, Br, or I;

Wherein R ⁴⁰ is C (O) H, C (O) C _1-4 alkyl, C (O) phenyl, C (O) benzyl, phenyl, benzyl, C _2-4 alkenyl, or SO ₂ CF ₃ ; Here, in C (O) -phenyl, C (O) benzyl, phenyl, and benzyl is C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI > is optionally substituted by one or more substituents selected; Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

Suitably, the compounds of formula (IIIyz) are the following compounds or salts or isotopic variations thereof:

(IIIyz)

(IIIyz)

Wherein X is Cl, Br, or I;

Wherein R ⁴⁰ is C (O) H, C (O) C _1-4 alkyl, C (O) phenyl, C (O) benzyl, phenyl, benzyl, C _2-4 alkenyl, or SO ₂ CF ₃ ; Here, in C (O) -phenyl, C (O) benzyl, phenyl, and benzyl is C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI > is optionally substituted by one or more substituents selected; Wherein Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

In one embodiment, a mixture of a compound of formula (IIIxz) and a compound of formula (IIIyz) is provided. In one embodiment, a mixture comprising a compound of formula (IIIxz) and a compound of formula (IIIyz) is provided.

The following embodiments, unless otherwise indicated, are intended to encompass compounds of formulas (Ia), (I), (IIa), (II), (IIIxa), (IIIx), (IIIya), Compounds of formula (IX), (IIIxz), (IIIyz), (IVa), (IV), (Va) ≪ / RTI > and intermediates.

Embodiments relating to individual R groups, Y groups, and X groups are contemplated to be fully combinable with one or more other R groups to form further embodiments of the present invention.

In one embodiment, R < ² > In one embodiment, R < ² > is halo. In one embodiment, R ² is OH. In one embodiment, R < ² > is a protected OH group. In one embodiment, R ² is a protected OH group that is not stable in a basic environment, so that treatment with the base converts the protected OH group to OH. Examples of such groups are well known in the art and include a group OC (O) R ¹⁴ , wherein R ¹⁴ is a group R ¹⁰ as defined above for formula (I), suitably C _1-6 Alkyl or benzyl, or C _1-6 alkyl or phenyl. In another embodiment, R < ² > is a protected OH group that is stable in a basic environment. Examples of such groups include OSi (R ¹⁶ ) ₃ wherein each R ¹⁶ is independently a group R ¹³ as defined above for general formula (I) and general formula (Ia), suitably C _Lt; / RTI > alkyl or phenyl. In one embodiment, Si (R ¹⁶⁾ ₃ is trimethyl silyl (TMS), triethylsilyl (TES), triphenylsilyl (TPS), tri-isopropyl-silyl (TIPS), teksil dimethylsilyl (TDS), tert- -butyldiphenylsilyl (TBDPS), tert - butyldimethylsilyl (TBDMS or TBS), di - tert - butyl-methyl-silyl (DTBMS), diethyl isopropyl silyl (DEIPS), and dimethyl-isopropyl-silyl (DMIPS), in particular TMS , TES, TIPS, TBDMS, and TBDPS.

In one embodiment, R ² is "up (up)" position, and that is beta-three-dimensional arrangement.

In one embodiment, Y is a bond.

(IIIa), (IIIx), (IIIyz), (IVa), (IIIx), , for a compound of and (IV), Y is _{C 1-20, C 1-12, C 1-10} , C 1-8, C 1-6, C 1-5, C 1-4, C 1- _3, or C _1-2 alkylene, or _{C 2-12, C 2-10, C 2-8} , C 2-6, C 2-5, C 2-4, C 2-3, or C ₂ alkenyl Nylene ring group, each of which is optionally substituted by one or more groups R < ³ > as defined above.

In one embodiment, in the case of the compound represented by the general formula (Va), (V), (VIa), (VI), (Xa), and (X), Y is C _1-20, C _1-12, C _{1 -10, C 1-8, C 1-6,} C 1-5, C 1-4, C 1-3, or C _1-2 alkylene is a linker group, which is at least one group as defined above and R ³ Lt; / RTI >

(IIIa), (IIIx), (IIIyz), (IVa), (IIIx), , And (IV), Y is a bond or a C _1-3 alkylene or C _2-3 alkenylene linker group, each of which is optionally substituted by one or more groups R ³ as defined above . Suitably Y is a C _1-3 alkylene or C _2-3 alkenylene linker group, each of which is optionally substituted by one or more groups R ³ as defined above.

In one embodiment, for compounds of formulas (Va), (V), (VIa), (VI), (Xa), and (X), Y is a bond or a C _1-3 alkylene linker group , Which is optionally substituted by one or more groups R < ³ > as defined above. Suitably Y is a C _1-3 alkylene linker group, which is optionally substituted by one or more groups R ³ as defined above.

(IIIa), (IIIx), (IIIyz), (IVa), (IIIx), , and the case of the compounds of (IV), Y is a _{bond, -CH 2 -, -CH 2 CH} 2 -, -CH = CH-, or _{-CH = C (CH 3) -} ; Preferably -CH ₂ - or a _{-CH = CH- -, -CH 2 CH} 2 -, -CH = CH-, or _{-CH = C (CH 3) -} , in particular -CH ₂ CH _2.

In one embodiment, in the case of the compound represented by the general formula (Va), (V), (VIa), (VI), (Xa), and (X), Y is a bond, -CH ₂ -, or -CH ₂ CH ₂ -; Suitably -CH ₂ - or -CH ₂ CH ₂ -, in particular -CH ₂ CH ₂ .

(IIIa), (IIIx), (IIIyz), (IVa), (IIIx), , And (IV), Y is a bond, an unsubstituted C _1-3 alkylene group, a C _1-3 alkylene group substituted by OH, or a C _1-3 alkenylene group. For example, Y is a _{bond, -CH 2 -, -CH 2 CH} 2 -, -CH (OH) -CH 2 -, -CH = CH-, or _{-CH = C (CH 3) -} , particularly a bond, _{-CH 2 -, -CH 2 -CH 2} -, -CH = CH-, or _{-CH = C (CH 3) -} , in particular _{-CH 2 -, -CH 2 -CH 2} -, -CH = CH-, or -CH = C (CH ₃₎ - may be.

In one embodiment, for compounds of formulas (Va), (V), (VIa), (VI), (Xa), and (X), Y is a bond, an unsubstituted C _1-3 alkylene group , Or a C _1-3 alkylene group substituted by OH. For example, Y is a _{bond, -CH 2 -, -CH 2 CH} 2 -, or -CH (OH) -CH ₂ - may be.

In one embodiment, Y is a C _1-15 alkylene linker, more preferably a C _1-12 , C _1-10 , or C _1-8 alkylene linker, substituted by an OH group. In this case, the linker Y is a group Y ⁴ -CH (OH) -CH ₂ , wherein Y ⁴ is as defined for Y, but the OH group is single from the R ⁴ moiety CH ₂ groups. For example, Y is -CH (OH) -CH ₂ - may be.

The Y linker is a compound of formula (I) wherein R ⁴ is CN or R ⁴ is CH (XR ¹⁰ ) (XR ¹¹ ) such as CH (OR ¹⁰ ) (OR ¹¹ ) wherein R ¹⁰ and R ¹¹ are as defined above, Especially XR ¹⁰ and XR ¹¹ , such as OR ¹⁰ and OR ¹¹ groups, together with the carbon atom to which they are attached, form a cyclic group, for example a cyclic acetal group such as 1,3-dioxane or 1,3-dioxolane ring Is formed.

In one embodiment, R < ³ > In one embodiment, R < ³ > is halo. In one embodiment, R < ³ > is OH. In one embodiment, R ³ is NR ⁸ R ⁹ , wherein each R ⁸ and R ⁹ is independently selected from among H, methyl, ethyl, benzyl, and tert -butyoxycarbonyl. In one embodiment, R < ³ > is a protected OH group. In one embodiment, R ³ is a protected OH group that is not stable in a basic environment, so that treatment with the base converts the protected OH group to OH. Examples of such groups are well known in the art and include a group OC (O) R ¹⁴ , wherein R ¹⁴ is a group R ¹⁰ as defined above for formula (Ia) or (I) C _1-6 alkyl or benzyl, or C _1-6 alkyl or phenyl. In another embodiment, R < ³ > is a protected OH group that is stable in a basic environment. Examples of such groups include OSi (R ¹⁶ ) ₃ wherein each R ¹⁶ is independently a group R ¹³ as defined above for formula (Ia) or (I), suitably C _{1- 6} alkyl or phenyl. In one embodiment, Si (R ¹⁶⁾ ₃ is trimethyl silyl (TMS), triethylsilyl (TES), triphenylsilyl (TPS), tri-isopropyl-silyl (TIPS), teksil dimethylsilyl (TDS), tert- -butyldiphenylsilyl (TBDPS), tert - butyldimethylsilyl (TBDMS or TBS), di - tert - butyl-methyl-silyl (DTBMS), diethyl isopropyl silyl (DEIPS), and dimethyl-isopropyl-silyl (DMIPS), in particular TMS , TES, TIPS, TBDMS, and TBDPS.

In one embodiment, R ³ is H, halo, OH, OC (O) R ¹⁴ , OSi (R ¹⁶ ) ₃ , or NR ⁸ R ⁹ ;

Wherein R ¹⁴ is C _1-6 alkyl or phenyl;

Each R ¹⁶ is independently C _1-6 alkyl or phenyl;

Each R ⁸ and R ⁹ is independently H, methyl, ethyl or tert -butoxycarbonyl.

In one embodiment, each R ³ is independently halo, OR ⁸ , or NR ⁸ R ⁹ ; Wherein each R ⁸ and R ⁹ is independently H or C _1-4 alkyl.

In one embodiment, each R ³ is independently halo, OR ⁸ , or NR ⁸ R ⁹ ; Wherein each R ⁸ and R ⁹ is independently selected from H, methyl, or ethyl, especially H or methyl.

In one embodiment, Y and R ⁴ together form a = CH ₂ group.

In one embodiment, when present in the R ₄ moiety, each R ¹⁰ and R ¹¹ is, independently,

a. Hydrogen;

b. C _1-10 alkyl, C _2-10 alkenyl, or C _2-10 alkynyl, any of which is optionally substituted by one or more substituents as defined above;

c. 6- to 10-membered aryl or 5- to 10-membered heteroaryl group, each of which is optionally substituted by one or more substituents as defined above;

d. A polyethylene glycol residue;

e. R ⁴ is ^{CH (XR 10) (XR 11} ), CH (R 10) (XR 11), NR 10 R 11, BR 10 R 11, CH [C (O) OR 10] 2, or CH (BR ¹⁰ R ¹¹ ) ₂ , the R ¹⁰ and R ¹¹ groups are taken together with the atoms or atoms to which they are attached to form a 3- to 10-membered heterocyclic ring, more preferably a 5- to 6-membered heterocyclic ring .

In one embodiment, each R < ¹⁰ > and R < ¹¹ >

a. Hydrogen;

b. C _1-10 alkyl, C _2-10 alkenyl, or C _2-10 alkynyl, any of which is optionally substituted by one or more substituents as defined above;

c. 6- to 10-membered aryl or 5- to 10-membered heteroaryl group, each of which is optionally substituted by one or more substituents as defined above;

d. A polyethylene glycol residue;

e. R ⁴ is ^{CH (OR 10) (OR 11} ), CH (R 10) (OR 11), CH (SR 10) (SR 11), NR 10 R 11, BR 10 R 11, CH [C (O) OR ¹⁰ ] ₂ , or CH (BR ¹⁰ R ¹¹ ) ₂ , the R ¹⁰ and R ¹¹ groups may be combined with the atoms or atoms to which they are attached to form a 3- to 10-membered heterocyclic ring.

Suitably, each R < ¹⁰ > and R < ¹¹ >

a. Hydrogen;

b. C _1-10 alkyl, C _2-10 alkenyl, or C _2-10 alkynyl optionally substituted by one or more substituents as described above;

c. A 6- to 10-membered aryl group or a 5- to 6-membered heteroaryl group optionally substituted by one or more substituents as described above;

e. When R ⁴ is C (O) NR ¹⁰ R ¹¹ or NR ¹⁰ R ¹¹ , the R ¹⁰ and R ¹¹ groups may be combined with the nitrogen to which they are attached to form a pyrrolidine or piperidine ring, or R ⁴ is CH XR ¹⁰ ) (XR ¹¹ ), for example CH (OR ¹⁰ ) (OR ¹¹ ), the XR ¹⁰ and XR ¹¹ groups together with the carbon to which they are attached form a ring; Suitably X is O and the ring is a 1,3-dioxane or a 1,3-dioxolane ring; When R ⁴ is BR ¹⁰ R ¹¹ , the R ¹⁰ and R ¹¹ groups are combined with the boron atom to which they are attached to form a bridged boron-containing ring, such as 9-BBN.

Suitably, each R < ¹⁰ > and R < ¹¹ >

a. Hydrogen;

b. C _1-10 alkyl, C _2-10 alkenyl, or C _2-10 alkynyl optionally substituted by one or more substituents as described above;

c. A 6- to 10-membered aryl group optionally substituted by one or more substituents as defined above;

e. When R ⁴ is C (O) NR ¹⁰ R ¹¹ or NR ¹⁰ R ¹¹ , the R ¹⁰ and R ¹¹ groups may be combined with the nitrogen to which they are attached to form a pyrrolidine or piperidine ring, or R ⁴ is CH OR ¹⁰ ) (OR ¹¹ ), the OR ¹⁰ and OR ¹¹ groups may be combined with the carbon atoms to which they are attached to form a 1,3-dioxane or 1,3-dioxolane ring; When R ⁴ is BR ¹⁰ R ¹¹ , the R ¹⁰ and R ¹¹ groups are combined with the boron atom to which they are attached to form a bridged boron-containing ring, such as 9-BBN.

In one embodiment, when R ⁴ is NR ¹⁰ R ¹¹ , R ¹⁰ is H or C _1-4 alkyl and R ¹¹ is a 5-10 membered heteroaryl group such as a tetrazol.

Other examples of R < ⁴ > groups include azides and tetrazoles.

When R ⁴ is an OSi (R ¹³⁾ _3, preferably each R ¹³ is independently,

a. C _1-10 alkyl, C _2-10 alkenyl, or C _2-10 alkynyl optionally substituted by one or more substituents as described above; or

b. 10-membered aryl or 5- to 10-membered heteroaryl groups optionally substituted by one or more substituents as described above.

More preferably, each R < ¹³ >

a. C _1-10 alkyl, C _2-10 alkenyl, or C _2-10 alkynyl optionally substituted by one or more substituents as described above; or

b. And a 6- to 10-membered aryl group optionally substituted by one or more substituents as described above.

Even more suitably, each R ¹³ is independently selected from C _1-10 alkyl or phenyl, each of which is optionally substituted as described above.

In one embodiment, each R ¹³ is independently selected from C _1-6 alkyl (especially methyl, ethyl, isopropyl, tert -butyl, hexyl) and phenyl.

In one embodiment, Si (R ¹³⁾ ₃ is trimethyl silyl (TMS), triethylsilyl (TES), triphenylsilyl (TPS), tri-isopropyl-silyl (TIPS), teksil dimethylsilyl (TDS), tert- -butyldiphenylsilyl (TBDPS), tert - butyldimethylsilyl (TBDMS or TBS), di - tert - butyl-methyl-silyl (DTBMS), diethyl isopropyl silyl (DEIPS), and dimethyl-isopropyl-silyl (DMIPS), in particular TMS , TES, TIPS, TBDMS, and TBDPS.

Suitable substituents for alkyl, alkenyl, and alkynyl groups R ¹⁰ and R ¹¹ is ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, SO 2 R 19, SO 3 R 19, OSO 3 ^{R 19, N (R 19)} 2, and 6-to 10-membered aryl, or a group comprising a 5- to 14-membered heteroaryl, each of which C _1-6 alkyl, C _1-6 haloalkyl, halo, NO ^{_{2, CN, oR 19, SO}} 2 R 19, SO 3 R 19, or N (R ¹⁹⁾ are optionally substituted by _2; Wherein R < ¹⁹ > is as defined above.

Similarly, suitable substituents for the alkyl, alkenyl, and alkynyl R ¹³ groups include halo, NO ₂ , CN, OR ¹⁹ , SR ¹⁹ , C (O) OR ¹⁹ , SO ₂ R ¹⁹ , SO ₃ R ¹⁹ , OSO ₃ ^{R 19, N (R 19)} 2, and 6-to 10-membered aryl, or a group comprising a 5- to 14-membered heteroaryl, each of which C _1-6 alkyl, C _1-6 haloalkyl, halo, NO ^{_{2, CN, oR 19, SO}} 2 R 19, SO 3 R 19, or N (R ¹⁹⁾ are optionally substituted by _2; Wherein R < ¹⁹ > is as defined above.

These R ¹⁰ and more suitable substituents for groups R ¹¹ is optionally substituted with halo as described ^{above, OR 19, C (O)} OR 19, N (R 19) 2, SO 3 R 19, OSO 3 R 19, or 6, - to include an 10-membered aryl, more suitable substituents for these groups R ¹³ is optionally substituted with halo as described ^{above, OR 19, C (O)} OR 19, N (R 19) 2, SO 3 R 19, OSO ₃ R ¹⁹ , or a 6- to 10-membered aryl group.

More preferred substituents for these R ¹⁰ , R ¹¹ , and R ¹³ groups include halo, C _1-4 alkyl, C _1-4 haloalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, C (O) OH, SO ₂ OH, -NH (C _1-4 alkyl), or -N (C _1-4 alkyl) ₂ ; Include, for example, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, C (O) OH, SO ₂ OH, amino, methylamino and dimethylamino.

More preferred substituents for these R ¹⁰ , R ¹¹ , and R ¹³ groups include halo, C _1-4 alkyl, C _1-4 haloalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, C (O) OH, SO ₂ OH, -NH ₂ , -NH (C _1-4 alkyl), or -N (C _1-4 alkyl) ₂ ; Include, for example, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, C (O) OH, SO ₂ OH, amino, methylamino and dimethylamino.

Suitable substituents for the aryl and heteroaryl groups R ¹⁰ and R ¹¹ include C _1-6 alkyl, C _1-6 haloalkyl, halo, NO _2, CN, OR ^19, SR ^19, or N (R ¹⁹⁾ ₂ .

Similarly, suitable substituents for the aryl and heteroaryl R ¹³ comprises C _1-6 alkyl, C _1-6 haloalkyl, halo, NO _2, CN, OR ^19, SR ^19, or N (R ¹⁹⁾ ₂ .

More preferred substituents for aryl and heteroaryl R ¹⁰ and R ¹¹ groups include C _1-4 alkyl, C _1-4 haloalkyl, halo, OR ¹⁹ , or N (R ¹⁹ ) ₂ ; Similarly, more suitable substituents for the aryl and heteroaryl R ¹³ groups include C _1-4 alkyl, C _1-4 haloalkyl, halo, OR ¹⁹ , or N (R ¹⁹ ) ₂ .

Particularly suitable substituents for the aryl and heteroaryl R ¹⁰ , R ¹¹ and R ¹³ groups are halo, C _1-4 alkyl, C _1-4 haloalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, -NH (C _1-4 alkyl), or -N (C _1-4 alkyl) ₂ .

Particular examples of substituents for the aryl and heteroaryl R ¹⁰ , R ¹¹ , and R ¹³ groups include fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, , And dimethylamino.

Each of R ^19, as is the organized group for R ¹⁰ and R ¹¹ are independently H, C _1-6 alkyl, C _1-6 haloalkyl, or a 6-to 14-membered aryl or 5- to 14- Membered heteroaryl group, each of which is optionally substituted by one or more substituents selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl.

Suitably, R ¹⁹ is H, C _1-6 alkyl, C _1-6 haloalkyl, or 6-haloalkyl optionally substituted by one or more substituents selected from halo, C _1-4 alkyl, and C _1-4 haloalkyl. To 10-membered aryl or a 5 to 10-membered heteroaryl group.

More preferably, R ¹⁹ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, or phenyl optionally substituted by one or more halo, C _1-4 alkyl, or C _1-4 haloalkyl substituents.

Particular examples of R ¹⁹ include H, methyl, ethyl, trifluoromethyl, or phenyl optionally substituted by one or more substituents selected from fluoro, chloro, methyl, ethyl, and trifluoromethyl.

As set forth above for group R ¹³ , each R ¹⁹ is independently H, C _1-6 alkyl, or C _1-6 haloalkyl. In one embodiment, R ¹⁹ is H or C _1-6 alkyl, such as C _1-4 alkyl, e.g., methyl or ethyl. Specific examples of R < ¹⁹ > include H, methyl, ethyl, or trifluoromethyl.

In some particularly suitable compounds of formula (Ia), R ⁴ is C (O) OR ¹⁰ , OR ¹⁰ , SO ₃ R ¹⁰ , OSO ₃ R ¹⁰ , Halo, CN, _{^{azido, OSi (R 13) 3,}} C (O) R 10, NR 10 C (O) NR 10 SO 2 R 11, NR 10 C (O) NR 10 SO 2 NR 10 R 11, NR ¹⁰ SO ₂ R ¹¹ , CH (XR ¹⁰ ) (XR ¹¹ ), CH [C (O) OR ¹⁰ ] ₂ , BR ¹⁰ R ¹¹ , or phthalimide.

In some particularly suitable compounds of formulas (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), (IVa), (Va) ⁴ is C (O) OR ¹⁰ , OR ¹⁰ , SO ₃ R ¹⁰ , OSO ₃ R ¹⁰ , Halo, CN, C (O) R ¹⁰ , CH (XR ¹⁰ ) (XR ¹¹ ), CH [C (O) OR ¹⁰ ] ₂ , or BR ¹⁰ R ¹¹ ; Each R ¹⁰ and R ¹¹ is independently H, C _1-6 alkyl, or benzyl;

When R ⁴ is CH (XR ¹⁰ ) (XR ¹¹ ) or BR ¹⁰ R ¹¹ , R ¹⁰ and R ¹¹ combine with the atoms or atoms to which they are attached to form a 3- to 10-membered heterocyclic ring Or;

R ⁴ is C (O) NR ¹⁰ R ¹¹ wherein each R ¹⁰ and R ¹¹ is independently C (O) OR ¹⁹ , OR ¹⁹ , SO ₃ R ¹⁹ , or OSO ₃ R ¹⁹ , R ¹⁹ is H.

General formula (I), (II), (IIIx), (IIIy), (IV), (V), (VI), and is in particularly suitable for some of the compounds of ^{(X) R 4 C (O} ) OR 10, OR ¹⁰ , SO ₃ R ¹⁰ , OSO ₃ R ¹⁰ , Halo, CN, C (O) R ¹⁰ , CH (OR ¹⁰ ) (OR ¹¹ ), CH [C (O) OR ¹⁰ ] ₂ , or BR ¹⁰ R ¹¹ ; Each R ¹⁰ and R ¹¹ is independently H, C _1-6 alkyl, or benzyl;

When R ⁴ is CH (OR ¹⁰ ) (OR ¹¹ ) or BR ¹⁰ R ¹¹ , R ¹⁰ and R ¹¹ combine with the atoms or atoms to which they are attached to form a 3- to 10-membered heterocyclic ring Or;

R ⁴ is C (O) NR ¹⁰ R ¹¹ wherein each R ¹⁰ and R ¹¹ is independently C (O) OR ¹⁹ , OR ¹⁹ , SO ₃ R ¹⁹ , or OSO ₃ R ¹⁹ and R ¹⁹ is H.

When R ⁴ is CH (XR ¹⁰ ) (XR ¹¹ ) and R ¹⁰ and R ¹¹ combine with the atoms or atoms to which they are attached to form a 3- to 10-membered heterocyclic ring, suitably R ⁴ is 3-5 membered heterocyclic ring, in particular a 5-membered heterocyclic ring, for example R < ⁴ >

, 및

중에서 선택되고, 특히

이다.

, And

, And in particular

to be.

When R ⁴ is CH (R ¹⁰ ) (XR ¹¹ ) and R ¹⁰ and R ¹¹ together with the atoms or atoms to which they are attached form a 3- to 10-membered heterocyclic ring, suitably R ³ is 3-membered heterocyclic ring, for example R < ⁴ >

, 및

중에서 선택되고, 특히

이다.

, And

, And in particular

to be.

Alternatively,

R ⁴ is ^{C (O) O -, O} -, SO 3 -, or OSO ₃ ^- or;

And R ⁴ is ^{C (O) NR 10 R 11} , where R ¹⁰ and R ¹¹ are independently ^{C (O) O -, O} -, SO 3 -, or OSO ₃ ^- compound that is substituted by the salt forms one ;

There is a counterion as described above for the base addition salt.

In one embodiment, R ⁴ is C (O) OR ¹⁰ , OR ¹⁰ , C (O) NR ¹⁰ R ¹¹ , SO ₃ R ¹⁰ , or OSO ₃ R ¹⁰ .

In one embodiment, R ⁴ is OSi (R ¹³ ) ₃ .

In one embodiment, R ⁴ is halo, CN, C (O) R 10, CH (XR 10) (XR 11), NR 10 R 11, BR 10 R 11, -CH = CH 2, -C≡CH, CH [C (O) OR ¹⁰ ] ₂ , or CH (BR ¹⁰ R ¹¹ ) _2, or Y and R ⁴ together form a = CH ₂ group.

In one embodiment, R ⁴ is halo, CN, C (O) R 10, CH (OR 10) (OR 11), NR 10 R 11, BR 10 R 11, -CH = CH 2, -C≡CH, CH [C (O) OR ¹⁰ ] ₂ , or CH (BR ¹⁰ R ¹¹ ) _2, or Y and R ⁴ together form a = CH ₂ group.

In one embodiment, R ⁴ is halo, CN, C (O) R 10, NR 10 R 11, BR 10 R 11, C (O) CH 2 N 2, -CH = CH 2, -C≡CH, CH ^{[C (O) OR 10]} 2, CH (BR 10 R 11) 2, ^{_{azide, NO 2, NR 10 C (}} O) NR 10 SO 2 R 11, C (O) NR 10 SO 2 R 11, CH (XR ¹⁰ ) (XR ¹¹ ), CH (R ¹⁰ ) (XR ¹¹ ) wherein each X is independently O, S, or NR ⁸ .

When R ⁴ is CH (XR ¹⁰ ) (XR ¹¹ ), X is suitably O or S, for example O. In these compounds, when R ¹⁰ and R ¹¹ combine to form a ring, it is suitably a 5- or 6-membered ring. More suitably both X moieties are O and R ¹⁰ and R ^{11 form} a 1,3-dioxane or 1,3-dioxolane ring.

When R ⁴ is CH (R ¹⁰ ) (XR ¹¹ ), X is suitably O or S, for example O.

In one embodiment, R < ⁴ > is a carboxylic acid analog.

In one embodiment, R ⁴ is tetrazole, substituted ^{_{tetrazoles, -SO 2 -NHR 10, C (}} O) NH-SO 2 R 10, and NHC (O) carboxylic acid is selected from NH-SO ₂ R ¹⁰ An acid analogue;

Wherein R ¹⁰ is as defined above for a compound of formula (Ia) or (I) and is suitably H, C _1-6 alkyl, C _3-7 cycloalkyl, or 6- to 14-membered aryl For example phenyl). Suitably, the substituted tetrazole is selected from the group consisting of C _1-4 alkyl, halo, OH, O (C _1-4 alkyl), or SO ₂ R ¹⁰ (for example SO ₂ (C _1-4 alkyl), SO ₂ -phenyl the tetra-substituted by boil down-tolyl) -, or SO _2.

When R < ⁴ > is a carboxylic acid analogue it is suitably a tetrazolyl group, for example tetrazol-1-yl or tetrazol-5-yl.

In one embodiment, R ⁴ is halo, CN, C (O) R 10, CH (XR 10) (XR 11), CH = CH 2, -C≡CH, CH [C (O) OR 10] 2, BR ¹⁰ R ^11, or Y and R ⁴ together form a = CH ₂ group.

In one embodiment, R ⁴ is halo, CN, C (O) R 10, CH (OR 10) (OR 11), CH = CH 2, -C≡CH, CH [C (O) OR 10] 2, BR ¹⁰ R ^11, or Y and R ⁴ together form a = CH ₂ group.

Suitably, R ⁴ is C (O) OR ¹⁰ , C (O) NR ¹⁰ R ¹¹ , SO ₃ R ¹⁰ , or OSO ₃ R ¹⁰ .

More preferably, R ⁴ is C (O) OR ¹⁰ , SO ₃ R ¹⁰ , or OSO ₃ R ¹⁰ and R ¹⁰ is H;

R ⁴ is C (O) NR ¹⁰ R ¹¹ substituted by C (O) OR ¹⁹ , SO ₃ R ¹⁹ , or OSO ₃ R ¹⁹ , and R ¹⁹ is H.

In a particularly suitable other compounds, R ⁴ is halo, CN, C (O) R 10, CH (OR 10) (OR 11), NR 10 R 11, CH [C (O) OR 10] 2, or azide, and ;

Wherein R ¹⁰ and R ¹¹ are as defined above but suitably each independently is H or C _1-10 alkyl, C _2-10 alkenyl, or C _2-10 alkynyl optionally substituted as described above, or R ⁴ If the NR ¹⁰ R ^11, R ¹¹ may also suitably be a heteroaryl group such as tetrazolyl or can; When R ⁴ is CH (OR ¹⁰ ) (OR ¹¹ ), the OR ¹⁰ and OR ¹¹ groups together with the carbon to which they are attached can form a cyclic acetal group, especially a 1,3-dioxane or a 1,3-dioxolane group have.

In another particularly suitable compound, R ⁴ is NR ¹⁰ C (O) NR ¹⁰ SO ₂ R ¹¹ or C (O) NR ¹⁰ SO ₂ R ¹¹ wherein R ¹⁰ and R ¹¹ are as described above, Independently, H or optionally substituted C _1-10 alkyl, C _2-10 alkenyl, or C _2-10 alkynyl, as described above.

In one embodiment, R ⁴ is ^{C (O) OR 10, OC} (O) R 10, C (O) NR 10 R 11, OR 10, OSi (R 13) 3, S (O) R 10, SO 2 _{^{R 10, OSO 2 R 10,}} SO 3 R 10, OSO 3 R 10, halo, CN, C (O) R 10, NR 10 R 11, C (O) CH 2 N 2, CH [C (O) OR ^10] _{2, ^{azide, NO 2, NR 10 C (}} O) NR 10 SO 2 R 11, C (O) NR 10 SO 2 R 11, CH (XR 10) (XR 11), CH (R 10) ( XR < ¹¹ >), or a carboxylic acid analogue such as a tetrazol.

In another embodiment, R ⁴ is ^{C (O) OR 10, OC} (O) R 10, C (O) NR 10 R 11, OR 10, OSi (R 13) 3, S (O) R 10, SO 2 _{^{R 10, OSO 2 R 10,}} SO 3 R 10, OSO 3 R 10, halo, CN, C (O) R 10, CH (OR 10) (OR 11), CH (R 10) (OR 11), CH (SR ¹⁰ ) (SR ¹¹ ), NR ¹⁰ R ¹¹ , C (O) CH ₂ N ₂ , CH [C (O) OR ¹⁰ ] ₂ , an azide or a carboxylic acid analogue such as a tetrazol.

In one embodiment, R ⁴ is ^{C (O) OR 10, CONR} 10 R 11, OSO 2 R 10, OSO 3 R 10, CN, ^{azide, OR 10, OSi (R 13} ) 3, CH [C (O ) OR ¹⁰ ] ₂ , CH (OR ¹⁰ ) (OR ¹¹ ), NR ¹⁰ CONR ¹⁰ SO ₂ R ^11, and NR ¹⁰ SO ₂ R ¹¹ and tetrazol.

In one embodiment, R ⁴ is ^{C (O) OR 10, OC} (O) R 10, OR 10, OSi (R 13) 3, OSO 2 R 10, halo, CN, C (O) R 10, NR 10 R ¹¹ , CH [(C (O) OR ¹⁰ )] ₂ , azide, C (O) NR ¹⁰ SO ₂ R ¹¹ CH (XR ¹⁰ ) (XR ¹¹ ); Phthalimide, tetrazole, or substituted tetrazole.

Other examples of R < ⁴ > groups include azides and tetrazoles.

In one embodiment, R < ⁵ > In one embodiment, R < ⁵ > is OH. In one embodiment, R < ⁵ > is a protected OH group. In one embodiment, R ⁵ is a protected OH group that is not stable in a basic environment, so that treatment with the base converts the protected OH group to OH. Examples of such groups are well known in the art and include the groups OC (O) R ¹⁴ as defined above wherein R ¹⁴ is a group of the formula (Ia) or (I) is a group R ^10. Particularly suitable R < ¹⁴ > groups are as defined above for R < ¹⁰ >, _C1-6alkyl such as methyl, or benzyl; Or C _1-6 alkyl, such as methyl, or phenyl. In another embodiment, R < ⁵ > is a protected OH group that is stable in a basic environment. Examples of such groups are well known in the art and include OSi (R ¹⁶ ) ₃ wherein each R ¹⁶ is independently a group R ¹³ as defined above for general formula (Ia) and (I) And is suitably C _1-6 alkyl or phenyl. In one embodiment, Si (R ¹⁶⁾ ₃ is trimethyl silyl (TMS), triethylsilyl (TES), triphenylsilyl (TPS), tri-isopropyl-silyl (TIPS), teksil dimethylsilyl (TDS), tert- -butyldiphenylsilyl (TBDPS), tert - butyldimethylsilyl (TBDMS or TBS), di - tert - butyl-methyl-silyl (DTBMS), diethyl isopropyl silyl (DEIPS), and dimethyl-isopropyl-silyl (DMIPS), in particular TMS , TES, TIPS, TBDMS, and TBDPS.

In one aspect of the present invention,

(6β, 7β, 22E) -6,7-epoxy-3-oxo-4,22-colladiene-24-oic acid ethyl ester (Example 1);

(6β, 7β, 20S) -6,7-epoxy-3-oxo-4,22-colladiene-24-oic acid ethyl ester (Example 5);

(6β, 7β, 20S) -6,7-epoxy-20-hydroxymethyl-pregna-4-en-3-one (Example 41);

(6β, 7β, 20S) -6,7-epoxy-20-bromomethyl-pregna-4-en-3-one (Example 42);

(20S) -methanesulfonyloxymethyl-6,7- [beta] -epoxy-4-prenenen-3-one (Example 43);

(20R) -cyanomethyl-6,7- [beta] -epoxy-4-prenenen-3-one (example 44);

(20S) -20-acetoxymethyl-6,7- [beta] -epoxy-pregna-4-en-3-one (example 45);

(6β, 7β, 20S) -6,7-epoxy-20- tert -butyldiphenylsiloxymethyl-pregna-4-en-3-one (Example 46);

(6β, 7β, 20S) -6,7-epoxy-20-azidomethyl-pregna-4-en-3-one (example 47);

(6β, 7β, 20S) -6,7-epoxy-20- ( N -phthalimidomethyl) -pregna-4,6-dien-3-one (example 48);

(6β, 7β, 20S) -6,7-epoxy-20-formyl-pregna-4-en-3-one (example 49);

(6β, 7β, 20S) -6,7-epoxy-20- (ethylene dioxymethyl) -pregna-4-en-3-one (Example 50); And

(6β, 7β) -6,7-epoxy-3-oxo-4-cholene-23-carboxy-24-oic acid dimethyl ester (Example 51);

(I) or a salt thereof or an isotopic variant thereof.

General formula ( Ia ) And the preparation of the compound of (I)

Epoxidation of dienones (IIA) using meta -chloroperoxybenzoic acid ( m CPBA) or magnesium monoperoxyphthalate (MMPP) is described in Uekawa et al., Biosci . Biotechnol . Biochem . 2004 , 68 , 1332-1337 (incorporated herein by reference) and is said to yield an alpha-epoxide as shown in Scheme 1.

Reaction 1 : Uekawa Condition

Starting from this alpha-epoxide, the inventors of the present invention have found that the present invention can be used in a wide range of applications, such as those described in patent applications PCT / GB2015 / 053516 (WO2016 / 079517), PCT / GB2015 / 053517 (WO2016 / 079518), PCT / GB2015 / 053518 A process for the synthesis of obethiolic acid and its analogs as described in US Pat. Nos. WO 01/16719, WO 201/1679519, and PCT / GB2015 / 053519 (WO2016 / 079520), all of which are incorporated herein by reference; Intermediates.

The present inventors have now devised alternative routes to oveticholic acid and its analogs using corresponding beta-epoxides.

The inventors have beta-but research additional conditions for the epoxidation of compound (IIA) in order to form an epoxide, peroxide (e.g. m CPBA or MMPP - Sikkim varying the conditions described Yiwu cars and the like), dimethyl-deoxy It has been found that reactions catalyzed by various catalysts, such as DMDO, and other substituted dioxiranes, as well as MTO or Mn (II) salts, all produce alpha-epoxides as the major diastereomers. Beta epoxide was observed, but the yield was typically less than 15%.

It is known that an alkene may be reacted to form a halohydrin, which in turn may undergo an intramolecular cyclization reaction upon treatment with a base to form an epoxide to form an epoxide. This reaction is described in Draper, RW, J. Chem . Soc . Perkin Trans. I , 1983 , 2781-2786 (incorporated herein by reference) in which 4,6-dien-3-one steroid molecules are reacted with chromyl chloride to form 6? -Chloro, 7? -Hydrin (As a single product): < RTI ID = 0.0 >

However, when treated with a base this compound will form an alpha (down) epoxide.

The present inventors have unexpectedly found that the compounds of formula (II) can be used as starting materials for the production of trichloroisocyanuric acid (TCCA) (TCCA), which is inexpensive and readily available, as described in J. Braz . .. Chem Soc 2002, 13 ( 5), 700-703];.... the literature [Org Proc Res Dev 2002, 6 (4), 384-393] 6,7- halo compound by gave high) reacting ( Beta-epoxide could be obtained in 40% yield through the formation of (IIIxA) or (IIIyA).

This reaction is described in Example 1.

Then, the halohydrin compound (IIIxA) or (IIIyA) is cyclized using a base, 1,8-diazabicycloundec-7-ene (DBU) to obtain the desired beta-epoxide (IA) Yield. This reaction is described in Example 2.

(IIIxA) or (IIIyA), since both of the compounds of (IIIxA) or (IIIyA) will be cyclized under basic conditions to form the same compound (IA) in the case of the cyclization reaction to form compound (IA) It should be noted that it is not necessary to check whether or not the < RTI ID = 0.0 >

Accordingly, one aspect of the present invention provides a process for preparing a compound of formula (Ia), comprising the steps of:

(A) Reacting a compound of formula (IIa) with a halogenating agent to provide a compound of formula (IIIxa) and / or a compound of formula (IIIya)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia)

And

(B) Reacting a compound of formula (IIIxa) and / or a compound of formula (IIIya) with a base to form a compound of formula (Ia)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia).

In another aspect of the present invention there is provided a process for preparing a compound of general formula (I), comprising the steps of:

(A) Compounds of formula (II) can be prepared by reacting compounds of formula (II) with trichloroisocyanuric acid (TCCA), tribromoisocyanuric acid (TBCA), triiodoisothiocyanuric acid (TICA), 1,3-dichloro-5,5-dimethylhydantoin Dibromo-5,5-dimethylhydantoin (DBDMH), or 1,3-diiodo-5,5-dimethylhydantoin (DIDMH) ≪ / RTI > and / or a compound of formula (IIIy)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (I);

And

(B) Reacting a compound of formula (IIIx) and / or a compound of formula (IIIy) with a base to form a compound of formula (I)

Wherein X is Cl, Br, or I;

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (I).

Suitably, step (B) is carried out using the crude halohydrin intermediate obtained from step (A) without further purification.

Accordingly, one aspect of the present invention provides a compound of formula (Ia), which comprises reacting a compound of formula (IIa) with a halogenating agent followed by reaction with a base to provide a compound of formula (Ia) Are provided:

               (IIa)    (Ia)

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined for the compound of formula (Ia), and the halogenating agent is as defined above.

In another aspect of the present invention, there is provided a process for the preparation of compounds of formula (II) in which TCCA, TIBA, TICA, , Dimethylhydantoin (DCDMH), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), or 1,3-diiodo-5,5-dimethylhydantoin (DIDMH) To give a compound of general formula (I) by reaction with a base followed by reaction with a base to give a compound of general formula (I)

                (II)     (I)

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of general formula (I).

References to the following steps (A) and (B) apply irrespective of whether the halohydrin intermediates are isolated and purified.

Suitable halogenating agents are those capable of forming a "positive _{halogen", Br 2, Cl 2,} 2, N - bromosuccinimide (NBS), N - chloro-succinimide (NCS), N - I ohdoseok god imide (NIS), chloramine -T (tosyl chloride la imide), tert - butyl hypochlorite, trichloro Roy SOCCIA press acid (TCCA), root rib feeders SOCCIA press acid (TBCA), tree iodo Doi SOCCIA press acid (TICA ), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) -Dimethylhydantoin (DIDMH). ≪ / RTI >

Suitable halogenating agents may also be Br ₂ , Cl ₂ , or di- tert -butyl peroxide with I ₂ in situ generated reagents, such as TiCl ₄ ; Ca (OCl) ₂ with NaCl in AcOH; Or TMSCl with H ₂ O ₂ .

Thus, in one embodiment, the halogenating agent is _{Br 2, Cl 2, I 2} , NBS, NCS, NIS, chloramine -T, tert - butyl hypochlorite, TCCA, TBCA, TICA, DCDMH, DBDMH, DIDMH, TiCl ₄ ≪ RTI ID = 0.0 > di- tert -butyl < / RTI > Ca (OCl) ₂ with NaCl in AcOH; Or TMSCl with H ₂ O ₂ . In particular, the halogenating agent is selected from NBS, NCS, NIS, chloramine-T, TCCA, TBCA, TICA, DCDMH, DBDMH, and DIDMH. For example, the halogenating agent is TCCA, TBCA, TICA, DCDMH, DBDMH, and DIDMH And selected, for example, from TCCA and tert -butyl hypochlorite, especially TCCA.

Tribromoisocyanuric acid (TBCA) and triiodoisocyanuric acid (TICA) are equivalents of trichloroisocyanuric acid (TCCA) and exhibit the following structure:

1,3-dibromo-5,5-dimethylhydantoin (DBDMH), and 1,3-diiodo-5,5-dimethyl Hydantoin (DIDMH) represents the following structure:

In step (A), the compound of formula (II) is suitably reacted with TCCA, TBCA, or TICA, particularly TCCA.

In one embodiment, in step (A) the compound of formula (II) is reacted with TCCA, TBCA, TICA, or tert -butyl hypochlorite, especially TCCA or tert -butyl hypochlorite, in particular TCCA.

Suitably, 0.1-2.2 equivalents, for example 0.2-1.5, 0.2-0.9, 0.2-0.6, or about 0.4 equivalents of a halogenating agent are used. Thus, in one embodiment, 0.1-2.2 equivalents, such as 0.2-1.5, 0.2-0.9, 0.2-0.6, or about 0.4 equivalents of a halogenating agent are used in step (A).

Halogenating agents such as TCCA, TBCA, TICA, DCDMH, DBDMH, or DIDMH are typically used in step (A), typically 0.1-2.2 equivalents, such as 0.1-0.9, 0.2-0.6, .

The reaction is suitably carried out in an organic solvent such as acetone, DMF, MeCN, or CH ₂ Cl ₂ , optionally mixed with an additive such as a co-solvent such as water and / or MeSO ₃ H or benzoic acid. Other suitable organic solvents include THF, t -butyl alcohol, acetic acid, dioxane, DMSO, and formic acid. In one embodiment, the reaction is carried out in a solvent selected from acetone, DMF, MeCN, or CH ₂ Cl ₂ , THF, t -butyl alcohol, acetic acid, dioxane, DMSO, formic acid, and water, and mixtures thereof. In one embodiment, the reaction solvent is a mixture of acetone and water. In one embodiment, the reaction solvent is pure formic acid. In one embodiment, the reaction solvent is pure acetic acid. In one embodiment, the reaction solvent comprises formic acid or acetic acid.

In one embodiment, the reaction is carried out in the presence of HOC (O) R ^x , HOR ^y , or HSO ₃ R ^z ; Wherein R ^x is H, C _1-4 alkyl (e.g., methyl or ethyl), phenyl or benzyl; R ^y is phenyl, benzyl, or C _2-4 alkenyl (e.g., allyl); R ^z is CF ₃ wherein phenyl and benzyl are optionally substituted with one or more substituents selected from C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI > In one embodiment, HOR ^x , HOR ^y , or HSO ₃ R ^z can be present as an additive in the reaction (suitably in the absence of water and in the presence of an aprotic solvent). In another embodiment, HOR ^x , HOR ^y , or HSO ₃ R ^z is present as the reaction solvent itself.

In embodiments wherein the reaction is carried out in the presence of HOC (O) R ^x , HOR ^y , or HSO ₃ R ^z as defined above in the absence of water or a quantum solvent, the compound of formula (IIa) or (II) By treatment with a halogenating agent, an intermediate compound of formula (IIIxz) and / or an intermediate compound of formula (IIIyz) (as defined hereinabove) will be formed. In situations where the group R < ⁴⁰ & gt ^; is not susceptible to the base, the process of forming a compound of formula (Ia) or (I) further comprises an additional step of removing the R < ^{40 &} gt ^; group prior to treatment with the base. For example, when OR ⁴⁰ is O-allyl (R ^y are formed by the reaction of the allyl HOR ^y) the allyl group can be removed by treatment with PdCl _2. This step for removing group R < ⁴⁰ > is in effect a deprotection step and is well known to those skilled in the art (see Wuts, PGM and Greene, TW (2006) "Greene's Protective Groups in Organic Synthesis" 4 see ^{th Edition, John Wiley & Sons,} Inc., Hoboken, NJ, USA]). A further example of this deprotection step is the case where OR < ⁴⁰ > is OPMB (PMB = paramethoxybenzyl, R ^y is formed by the reaction of HOR ^y with paramyoxybenzyl) and the PMB group is DDQ (2,3- -5,6-dicyano- p -benzoquinone).

Suitably the reaction is carried out at a temperature of from -40 ° C to 50 ° C, for example from 0 ° C to room temperature (for example 18 ° C), or at 0 ° C, or at room temperature (for example at 18 ° C).

In one embodiment, step (A) comprises reacting a compound of general formula (IIIxa) with a halogenating agent such as TCCA, TBCA, TICA, DCDMH, DBDMH, or DIDMH, Is a reaction of a compound of formula (IIa) or a compound of formula (II). In one embodiment, step (A) comprises reacting a halogenating agent, such as TCCA, TBCA, TICA, DCDMH, DBDMH, or DIDMH, with a halogenating agent, such as, for example, (IIa) or a compound of formula (II). In one embodiment, step (A) comprises providing a mixture of a compound of formula (IIIxa) and a compound of formula (IIIya), or a compound of formula (IIIx) and a compound of formula (IIIy) For example, TCCA, TBCA, TICA, DCDMH, DBDMH, or DIDMH with a compound of formula (IIa) or a compound of formula (II).

In step (B), suitable bases include KOH, NaOH, NaOMe, NaOEt, NaCO _3, K ₂ CO _3, and a non-nucleophilic base, such as N, N-diisopropylethylamine (DIPEA), 1,8- Diazabicyclo dox-7-ene (DBU), and 2,6-di- tert -butylpyridine. Suitably DBU is present in CH ₂ Cl ₂ , NaOEt in THF and K ₂ CO ₃ in EtOH or MeOH. Suitable bases will be known to those skilled in the art. In one embodiment, the base is DBU. Suitably 1-2 equivalents, such as about 1.5 equivalents of base are used in the reaction.

In one embodiment, step (B) is the reaction of a compound of formula (IIIxa) or a compound of formula (IIIx) with a base to provide a compound of formula (Ia) or a compound of formula (I) . In one embodiment, step (B) is the reaction of a compound of formula (IIIya) or a compound of formula (IIIy) with a base to provide a compound of formula (Ia) or a compound of formula (I), respectively. In one embodiment, step (B) comprises reacting a mixture of a compound of formula (IIIxa) and a compound of formula (IIIia), respectively, with a base to provide a compound of formula (Ia) (IIIx) and a compound of formula (IIIy).

The reaction is suitably carried out in an organic solvent such as acetone, DMF, MeCN, or CH ₂ Cl ₂ , optionally mixed with an additive such as a co-solvent such as water and / or MeSO ₃ H or benzoic acid. Other suitable organic solvents include THF, t -butyl alcohol, acetic acid, dioxane, DMSO, and formic acid. In one embodiment, the reaction is carried out in a solvent selected from acetone, DMF, MeCN, or CH ₂ Cl ₂ , THF, t -butyl alcohol, acetic acid, dioxane, DMSO, formic acid, and water, and mixtures thereof. In one embodiment, the reaction solvent is a mixture of acetone and water. In one embodiment, the reaction solvent is pure formic acid. In one embodiment, the reaction solvent is pure acetic acid. Suitably the reaction is carried out at a temperature of from -40 ° C to 50 ° C, for example from 0 ° C to room temperature (for example 18 ° C), or at 0 ° C, or at room temperature (for example at 18 ° C).

In one embodiment, the compound of formula (II) is reacted with trichloroisocyanuric acid (TCCA) or tert -butyl hypochlorite, or with DBDMH (especially trichloroisocyanuric acid (TCCA) or tert -butyl hypochlorite) There is provided a process for preparing a compound of general formula (I) which comprises reacting a compound of general formula (I) with a base to give a compound of general formula (I)

                 (II)           (I)

Wherein Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of general formula (I)

Wherein the reaction is carried out in a solvent selected from acetone, water, formic acid, acetic acid, and mixtures thereof, in particular a mixture of acetone and water, pure formic acid, or pure acetic acid.

In this embodiment, the halohydrin intermediate (s) is isolated prior to reaction with the base, but not purified.

This process for forming the beta-epoxide is expected, at least in some embodiments, to exhibit one or more of the following advantages:

* Good position-selectivity and stereoselectivity;

* Simplified procedures;

* Low cost.

General formula ( IIa ) And < RTI ID = 0.0 > (II) <

The compound of formula (IIa) or the compound of formula (II) can be prepared from a compound of formula (VIIa) or a compound of formula (VII), respectively, by reaction with an oxidizing agent such as chloranil:

(VIIa)/(VII)

(VIIa) / (VII)

Wherein Y, R ² , R ⁴ and R ⁵ are as defined above for formula (Ia) (for formula (VIIa)) or for formula (I) ) ≪ / RTI > as defined above.

The reaction may be carried out under acidic conditions, for example in the presence of acetic acid, and in an organic solvent such as toluene.

Some compounds of the general formulas (IIa), (II), (VIIa) and (VII) are known. See, e.g., Uekawa et al., Biosci . Biotechnol . Biochem . , 2004, 68, 1332-1337] ( 22 E) -3- oxo -4,22- coke diene -24- Osan ethyl ester (compound (VIIA)) is from stigmasterol (incorporated herein by reference) (22 E) that represents the formula: then the synthesis-3-oxo -4,6,22- coke triene -24- Osan ethyl ester, whose conversion to (herein referred to as compounds (IIA)) are described in have:

(IIA)

(IIA)

Other compounds of formulas (IIa), (II), (VIIa), and (VII) can be prepared by analogous methods from phytosterols analogous to stigmasterol. Stigmasterol and other phytosterols are plant sterols and are readily available or can be prepared by known routes.

Compounds of general formula (VIIa) or compounds of general formula (VII) may also be prepared from compounds of general formula (VIIIa) or general formula (VIII), respectively, by reaction with bases such as lithium bromide and lithium carbonate Can be prepared by:

(VIIIa)/(VIII)

(VIIIa) / (VIII)

Wherein Y, R ² , R ⁴ and R ⁵ are as defined in formula (Ia) (in case of formula (VIIIa)) or in formula (I) Same as. The reaction may be carried out in a solvent such as N, N -dimethylformamide (DMF) and at a temperature of about 120-180 < 0 > C. Such a reaction is described in Example 10 of patent application WO2016 / 079517 (incorporated herein by reference).

The compounds of the general formula (VIIIa) or the compounds of the general formula (VIII) can be prepared by bromination of the compounds of the general formula (IXa) respectively or by bromination of the compounds of the general formula (IX), for example bromine in acetic acid Can be obtained by:

(IXa)/(IX)

(IXa) / (IX)

Wherein Y, R ² , R ⁴ and R ⁵ are as defined in formula (I) (in case of formula (IXa)) or in formula (Ia) Same as. This reaction is described in Example 9 of patent application WO2016 / 079517 (incorporated herein by reference).

The compounds of the general formula (IXa) or the compounds of the general formula (IX) can be prepared from compounds of the general formula (XIa) or the compounds of the general formula (XI), typically by oxidation with a chromium-based oxidizing agent or sodium hypochlorite, respectively have:

(XIa)/(XI)

(XIa) / (XI)

Y, R ² , R ⁴ and R ⁵ are as defined in formula (Ia) (in case of formula (XIa)) or in formula (I) Same as. This reaction is described in Example 8 of patent application WO2016 / 079517 (incorporated herein by reference).

Compounds of formula (IXa) and compounds of formula (IX) wherein R ⁴ is C (O) OR ¹⁰ , wherein R ¹⁰ is C _1-6 alkyl or benzyl, or C _1-6 alkyl or phenyl, Can be prepared from a compound of general formula (IXa) wherein R ⁴ is C (O) OH and a compound of general formula (IX), typically by esterification by reaction with an appropriate alcohol under acidic conditions.

Compounds of general formula (XIa) wherein R ⁴ is C (O) OH and R ⁵ is H and compounds of general formula (XI) can be prepared from compounds of general formula (XIIa) and general formula (XII) , And by reaction with a reducing agent, typically hydrazine, in an alcoholic or glycolic solvent such as diethylene glycol: < RTI ID = 0.0 >

(XIIa)/(XII)

(XIIa) / (XII)

Wherein R ² and Y are as defined for formula (Ia) (for formula (XIIa)) and are as defined for formula (I) (for formula (XII));

R ⁴ is C (O) OR ¹⁰ , wherein R ¹⁰ is C _1-6 alkyl or benzyl;

OR ¹² is protected OH.

If OR < ¹² > is a protected OH group that is stable under basic conditions, this reaction may lead to the removal of the protecting group R < ¹² >

OH is discussed above, for example, R ¹² can be the group C (O) R ¹⁴ , wherein R ¹⁴ is as defined above, especially C _1-6 alkyl or benzyl; Or C _1-6 alkyl or phenyl. And silyl ether is also suitable, in this case, R ¹² is a group Si (R ¹⁶⁾ may be _3, each R ¹⁶ herein is a group as defined above independently or in particular R ¹³ C _1-6 alkyl or phenyl to be. Other suitable protecting groups for OH are well known to those skilled in the art (see Wuts, PGM and Greene, TW (2006) "Greene's Protective Groups in Organic Synthesis", 4 ^th Edition, John Wiley & Sons , Inc., Hoboken, NJ, USA).

Particularly suitable R < ¹² > groups include unstable groups in the presence of a base, since this eliminates the need for an additional step of removing the protecting group. Examples of the group R ¹² is not stable in basic conditions is a group R ¹⁴ C (O), where R ¹⁴ is as defined above, especially C _1-6 alkyl or benzyl, or C _1-6 alkyl or phenyl .

Alternatively, a compound of formula (XIIa) or a compound of formula (XII) can be reacted with a compound of formula (XXXII) to give a compound of formula (XXXIIIa) or a compound of formula (XXXIII) The reaction may be carried out in two steps so that reduction by the reducing agent follows:

_{^{R 20 -NH-NH 2 (XXXII}} )

(Wherein R < ²⁰ > is a leaving group such as toluenesulfonyl or methanesulfonyl)

(XXXIIIa)/(XXXIII)

(XXXIIIa) / (XXXIII)

Wherein R ² and Y are as defined in formula (Ia);

R ⁴ and R ¹² are as defined for formula (XIIa);

R ²⁰ is as defined for formula (XXXII) (for both formula (XXXIIIa));

Wherein R ² and Y are as defined in formula (I);

R ⁴ and R ¹² are as defined for formula (VII);

R ²⁰ is as defined for formula (XXXII) (for both formula (XXXIII)). Examples of reducing agents that can be used in this reaction include hydrides such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride and the like. In the general formulas (XXXIIIa) and (XXXIII), R ²⁰ is as defined above for the compound of the general formula (XXXII), and Y, R ² , R ⁴ and R ¹² are each as defined for the compound of the general formula (XIIa) And (XII). ≪ / RTI >

The compound of formula (XIIa) or the compound of formula (XII) can be prepared from a compound of formula (XIIIa) or a compound of formula (XIII), respectively, by reaction with an oxidizing agent, for example sodium hypochlorite Can:

(XIIIa)/(XIII)

(XIIIa) / (XIII)

Wherein R ² and Y are as defined in formula (Ia) (in case of formula (XIIIa)) or as defined in formula (I) (in case of formula (XIII));

R ⁴ is C (O) OR ¹⁰ , wherein R ¹⁰ is C _1-6 alkyl or benzyl;

R ¹² is as defined above for formula (XIIa) (for formula (XIIIa)) or as defined above for formula (XXII) (for formula (XIII)); Is suitably -C (O) C _1-6 alkyl. Such a reaction is described in Example 5 of patent application WO2016 / 079517 (incorporated herein by reference).

The reaction may be carried out under acidic conditions, for example in the presence of acetic acid, and in an organic solvent such as ethyl acetate.

The compound of the general formula (XIIIa) or the compound of the general formula (XIII) can be prepared from the compound of the general formula (XIVa) or the compound of the general formula (XIV) by reaction with a medicament suitable for introducing the protecting group R ¹² Can:

(XIVa)/(XIV)

(XIVa) / (XIV)

Wherein R ² and Y are as defined above for formula (Ia) (for formula (XIVa)) or as defined for formula (I) (for formula (XIV));

R ⁴ is C (O) OR ¹⁰ , wherein R ¹⁰ is C _1-6 alkyl or benzyl. For example, when R ¹² is C (O) R ¹⁴ , the compound of formula (XIXa) or a compound of formula (XIXa), suitably in the presence of a weak base such as pyridine, catalyzed by 4-dimethylaminopyridine XIX) can be reacted with a carboxylic acid anhydride or an acid chloride. The reaction may be carried out in a solvent such as ethyl acetate. Such a reaction is described in Example 5 of patent application WO2016 / 079517 (incorporated herein by reference).

The compound of formula (XIVa) or the compound of formula (XIV) can be prepared by esterification of a compound of formula (XVa) or a compound of formula (XV), respectively:

(XVa)/(XV)

(XVa) / (XV)

Wherein R ² and Y are as defined in formulas (Ia) and (I).

The esterification reaction can be carried out by reacting an acid of formula (XVa) or formula (XV) with a suitable alcohol under acidic conditions. This reaction is described in Example 5 of the patent application PCT / GB2015 / 053516 (incorporated herein by reference).

Compounds of formula (XVa) and formula (XV) are known. For example, the compound of formula (XVa) or formula (XV) wherein Y is -CH ₂ CH ₂ - and R ² is H is deoxycholic acid (referred to herein as compound (XVA)), It is readily available from multiple sources.

An alternative route to compounds of the general formula (VIIa) and compounds of the general formula (VII) wherein R ⁴ is a gaseous ester is as shown in Scheme 2 wherein 4-androstanedione is R ² and R ⁵ Is H; Is converted to a compound of formula (VIIa) or formula (VII) wherein R ⁴ is -C (O) OCH ₃ and Y is -CH ₂ CH ₂ - or -CH = CH-.

Scheme 2

Other compounds having different values for Y and R < ² > can be used as alternative materials.

An alternative route to a compound of formula (IIa) wherein Y is an alkenylene group and to a compound of formula (II) is an olefination reaction using a compound of formula (XVII), for example, Or by the use of the Horner-Wadsworth-Emmons (HWE) olefination of the compound of formula (XVI)

(XVIa)/(XVI)

(XVIa) / (XVI)

Wherein R ² and R ⁵ are as defined for general formula (Ia) and general formula (I);

(XVII)

(XVII)

Wherein R < ¹⁰ > is as defined for formula (I).

The reaction can be carried out under standard HWE conditions, for example using a base such as sodium hydride.

Alternatively, the compounds of using HWE olefination R ⁴ is C (O) H of the formula (XI), (IX), (VIII), (VII), and (II) Y is a alkenylene group compound You can switch.

Compounds of formula (XVII) are readily available or can be prepared by methods known to those skilled in the art.

Other olefination reactions such as Tebbe olefination, Wittig type olefination, or Julia-Kocienski olefination can also be carried out by reacting a compound of formula (IIa), wherein Y is an alkenylene group, (II). ≪ / RTI > These olefination reactions are familiar to those skilled in the art.

The compound of the general formula (XVIa) or the compound of the general formula (XVI) can be prepared by reacting the compound of the general formula (XVIIIa) or the compound of the general formula (XVIII) with ozone, respectively:

(XVIIIa)/(XVIII)

(XVIIIa) / (XVIII)

Wherein R ² and R ⁵ are as defined for general formula (Ia) and general formula (I), and R ¹⁵ is C _1-6 alkyl.

An example of this type of reaction is provided in patent US 2,627,748 A (Levin et al. ), Incorporated herein by reference.

The compound of formula (XVIIIa) or the compound of formula (XVIII) can be prepared by reacting an acid with a compound of formula (XIXa) or a compound of formula (XIX) respectively in a solvent such as methanol:

(XIXa)/(XIX)

(XIXa) / (XIX)

Wherein R ² and R ⁵ are as defined for general formula (Ia) and general formula (I), and R ¹⁵ is C _1-6 alkyl.

The compound of formula (XIXa) or the compound of formula (XIX) can be prepared by oxidation of a compound of formula (XXa) or of a compound of formula (XX), respectively, using an Oppenauer oxidation Can:

(XXa)/(XX)

(XXa) / (XX)

Wherein R ² and R ⁵ are as defined for general formula (Ia) and general formula (I), and R ¹⁵ is C _1-6 alkyl.

Examples of the conversion of a compound of formula (XXa) to a compound of formula (XVIIIa) and of a compound of formula (XX) to a compound of formula (XX) are described in Shepherd et al , J. Am. Chem . Soc . 1955, 77 , 1212-1215 and Goldstein, J. Med . Chem . 1996 , 39 , 5092-5099, both of which are incorporated herein by reference.

One example of a compound of formula (XXa) and formula (XX) is fungal sterol ergosterol (referred to herein as (XXA)), wherein R ² and R ⁵ are both H and Y Shows the conversion of ergosterol to a compound of formula (II) wherein R = CH = CH ₂ and R ⁴ is C (O) OR ¹⁰ , wherein R ¹⁰ is ethyl.

Scheme 3

Compounds of general formula (Ia) and (IIa) wherein R ⁴ is C (O) R ¹⁰ , C (O) NR ¹⁰ R ¹¹ , S (O) R ¹⁰ , SO ₃ R ¹⁰ or OSO ₃ R ¹⁰ , Compounds of formulas (I) and (II) may be prepared from the corresponding compounds wherein R < ⁴ > is C (O) OR < ¹⁰ >, by reaction with appropriate reagents using methods known to those skilled in the art. For example, the methods described in WO2008 / 002573 and WO2010 / 014836 or the methods described in Classon et al , J. Org . Chem . , 1988 , 53 , 6126-6130 and Festa et al , J. Med . Chem ., 2014 , 57 , 8477-8495), all of which are incorporated herein by reference.

Subsequent reactions of compounds of general formula (IA) and (I)

General formula ( Ia ) And the compound of formula (I) Ovethicol  And Ovethicol  Processes for forming analogs

The compounds of formula (Ia) and formula (I) are useful in the synthesis of compounds of formula (Xa) and of compounds of formula (X) or salts or isotopic variations thereof, respectively:

(Xa)/(X)

(Xa) / (X)

In this formula,

R ¹ is C _1-4 alkyl, C _2-4 alkenyl, or C _2-4 alkynyl optionally substituted by one or more substituents selected from halo, OR ⁶ , and NR ⁶ R ⁷ (Formula (Xa) In the case of);

R ¹ is C _1-4 alkyl optionally substituted by one or more substituents selected from halo, OR ⁶ and NR ⁶ R ⁷ (for formula (X));

Wherein each R ⁶ and R ⁷ is independently H or C _1-4 alkyl;

R ² is H, halo, or OH;

Y ¹ is a bond or a C _1-20 alkylene linker group optionally substituted by one or more R ³ ;

Y ¹ and R ⁴ together form a = CH ₂ group;

R < ^5a > is H or OH;

Wherein R ³ and R ⁴ are as described above for a compound of formula (Ia) or (for formula (Xa)) as described above for a compound of formula (I) ).

Compounds of formula (Xa) and formula (X) are potent agonists of FXR and TGR5 and include obeticol acid, wherein R ¹ is ethyl, R ² and R ^5a are both H, Y ¹ is -CH ₂ CH ₂ -, and the compounds of formula (Xa) and (X) in R ⁴ is C (O) OH.

Compounds of general formula (Ia) or compounds of general formula (I) can be obtained via intermediates of general formulas (IVa), (IV), (Va), (V), (VIa) Can be converted into a compound of formula (Xa) or a compound of formula (X), respectively, in a four step process.

In one aspect of the present invention there is provided a process for the preparation of a compound of formula (Ia), (IVa), (Va), (Va) There is provided a process for preparing a compound of formula (Xa) from a compound of formula (Ia) further comprising at least one optional step of converting a compound of formula (Xa), (VIa)

(a) Optionally alkylating the compound of formula (Ia) with an organometallic reagent to provide a compound of formula (IVa)

(IVa)

(IVa)

Wherein R < ¹ > is as defined for a compound of formula (Xa);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia);

(b) Reduction of the compound of formula (IVa) using a suitable reducing agent to provide the compound of formula (Va)

(Va)

(Va)

(Wherein, R ¹ and Y ¹ are as defined for a compound of formula (Xa);

R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia);

(c) Oxidizing the compound of formula (Va) using a suitable oxidizing agent to provide a compound of formula (VIa)

(VIa)

(VIa)

(Wherein, R ¹ and Y ¹ are as defined for a compound of formula (Xa);

R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia);

(d) reducing the compound of formula (VIa) using a suitable reducing agent and removing the protecting group (s) when R ² and / or R ⁵ is protected OH, Wherein removal of the protecting group may take place before or after reduction.

Any stage following general formula (Ia), (IVa), (Va), (VIa), by reacting a compound side chain of and (Xa) alternative Y and / or R ⁴ compound with a moiety as described As shown in FIG.

In another aspect of the present invention there is provided a process for the preparation of a compound of general formula (I), (IV), (V), (V) There is provided a process for preparing a compound of formula (X) from a compound of formula (I) further comprising at least one optional step of converting a compound of formula (I), (VI)

(a) Optionally alkylating the compound of formula (I) with an organometallic reagent to provide a compound of formula (IV)

(IV)

(IV)

Wherein R < ¹ > is as defined for a compound of formula (X);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (I);

(b) Reduction of the compound of formula (IV) using a suitable reducing agent to provide the compound of formula (V)

(V)

(V)

(Wherein, R ¹ and Y ¹ are as defined for a compound of formula (X);

R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (I);

(c) Oxidizing the compound of formula (V) using a suitable oxidizing agent to provide the compound of formula (VI)

(VI)

(VI)

(Wherein, R ¹ and Y ¹ are as defined for a compound of formula (X);

R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (I);

(d) reducing the compound of formula (VI) using a suitable reducing agent and removing the protecting group (s) when R ² and / or R ⁵ is protected OH, Wherein removal of the protecting group may take place before or after reduction.

Any stage following general formula (I), (IV), (V), (VI), and reacting the side chain of the compound of (X) alternate Y and / or R ⁴ compound with a moiety as described As shown in FIG.

An example of step (a) is shown in Example 6, an example of step (b) is shown in Example 7, and an example of step (c)

In one embodiment, compounds of formula (IVa) are provided:

(IVa)

(IVa)

Wherein R < ¹ > is as defined for a compound of formula (Xa);

Y, R ² , R ⁴ , and R ⁵ are as defined for a compound of formula (Ia). Suitably R ⁴ in the compound represented by the general formula (IVa) is ^{C (O) OR 10, CONR} 10 R 11, OSO 2 R 10, OSO 3 R 10, CN, ^{azide, OR 10, OSi (R 13} ) 3, ^{CH [C (O) oR 10} ] 2, CH (oR 10) (oR 11), NR 10 CONR 10 SO 2 R 11, NR 10 SO 2 R 11, or tetra boil down.

In one embodiment there is provided a compound of formula Va:

(Va)

(Va)

Wherein R, R ¹ and Y ¹ are as defined for a compound of formula (Xa);

R ² , R ⁴ , and R ⁵ are as defined for compounds of formula (Ia). Suitably R ⁴ in the compound of formula (Va) are ^{C (O) OR 10, CONR} 10 R 11, OSO 2 R 10, OSO 3 R 10, CN, ^{azide, OR 10, OSi (R 13} ) 3, ^{CH [C (O) oR 10} ] 2, CH (oR 10) (oR 11), NR 10 CONR 10 SO 2 R 11, NR 10 SO 2 R 11, or tetra boil down.

(V) / (b) prepared as described above (steps (a) and (b)) were added to a solution of (5?, 6 ?, 7?) - 6- ethyl- (Va)) is a compound of the formula (3a, 5p, 6a, 7p) -6-ethyl-3,7-dihydroxy-cholan-24-oic acid, obetic acid Can be used for synthesis. This is described in Example 21.

Compounds of general formula (Xa) and general formula (X) are potent agonists of FXR and TGR5, in particular compounds wherein R < ¹ > is ethyl. The following is also included.

Compounds wherein R < ⁴ > is C (O) OH, for example,

Compounds of formula (Xa) / (X) wherein R ¹ is ethyl, R ² and R ^5a are both H, Y ¹ is -CH ₂ CH ₂ - and R ⁴ is C Beticholic acid; And

(Xa) / (X) wherein R ¹ is ethyl, R ² and R ^5a are both H, Y ¹ is -CH ₂ CH (CH ₃ ) - and R ⁴ is C compound; And

(Xa) / (X) wherein R ¹ is ethyl, R ² is H, R ^5a is OH, Y ¹ is -CH ₂ CH (CH ₃ ) - and R ⁴ is C / RTI >

* R ⁴ is OSO ₃ H or a salt thereof, for example,

(Xa) / (X) wherein R ¹ is ethyl, R ² and R ^5a are both H, Y ¹ is -CH ₂ CH ₂ - and R ⁴ is OSO ₃ H or a salt thereof; And

(Xa) / (X) wherein R ¹ is ethyl, R ² is H, R ^5a is OH, Y ¹ is -CH ₂ CH ₂ CH ₂ - and R ⁴ is OSO ₃ H or Its salt; And

(Xa) / (X) wherein R ¹ is ethyl, R ² is OH, R ^5a is H, Y ¹ is -CH ₂ CH ₂ - and R ₄ is OSO ₃ H or a salt thereof .

The compounds of formulas (Ia), (Xa), (IVa), (Va) and (VIa) and the compounds of formulas (I), (X), (IV), (V) , More suitable values for R < ⁴ > are as defined for general formulas (Ia) and (I), respectively.

In some compounds of the general formulas (Xa), (Va) and (VIa) or in some compounds of the general formulas (X), (V) and (VI), Y ¹ is a bond.

In other compounds of formulas (Xa), (Va) and (VIa) or other compounds of formulas (X), (V) and (VI), Y ¹ is a C _1-15 alkylene linker group, Suitably a C _1-12 , C _1-10 , or C _1-8 alkylene linker group and is optionally substituted by one or more R ³ as defined above. Typically each R ³ is independently halo, OR ⁸ , or NR ⁸ R ⁹ ; Wherein each R ⁸ and R ⁹ is independently selected from H, methyl or ethyl, especially H or methyl.

In some suitable compounds of the general formulas (Xa), (Va) and (VIa) or in some suitable compounds of general formulas (X), (V) and (VI), Y ¹ is an unsubstituted C _1-15 alkyl alkylene or C _2-15 alkenylene linker, more preferably C _1-12 alkylene, C _1-10 alkylene or C _1-8 alkylene, or C _2-12 alkenylene, C _1-10 alkenylene, or C _1-8 alkenylene.

Suitable compounds of the general formulas (Ia), (Xa), (IVa), (Va) and (VIa) or of the general formulas (I), (X), (IV), (V) In the compounds, R ¹ can be C _1-4 alkyl optionally substituted with one or more substituents selected from halo, OR ⁶ , or NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are each independently H, methyl Or ethyl, especially H or methyl. More preferably, R ¹ is unsubstituted C _1-4 alkyl.

Step (a)

To provide compounds of formula (IVa), compounds of formula (IVa) may be prepared from compounds of formula (Ia) by selective alkylation with an organometallic reagent:

(Ia)

(Ia)

Wherein R ² , R ⁴ , R ⁵ , and Y are as defined above;

(IVa).

(IVa).

Suitably the compound of formula (Ia) is < RTI ID = 0.0 >

(Ia)

(Ia)

Wherein R ² , R ⁴ , R ⁵ , and Y are as defined above.

To provide compounds of formula (IV), compounds of formula (IV) may be prepared from compounds of formula (I) by selective alkylation with an organometallic reagent:

(I)

(I)

Wherein R ² , R ⁴ , R ⁵ , and Y are as defined above;

(IV).

(IV).

Suitably, the compounds of formula (I) are the following compounds:

(I)

(I)

Wherein R ² , R ⁴ , R ⁵ , and Y are as defined above.

Suitable organometallic reagents include Gilman reagents formed by the reaction of an alkyl lithium compound of formula (XXI) with a copper (I) salt, especially a copper (I) halide, such as copper (I) iodide:

R ¹ -Li (XXI)

Wherein R < ¹ > is as defined for formula (Xa) or (X).

The reaction may be carried out in an organic solvent such as tetrahydrofuran, other ethers such as diethyl ether, or mixtures thereof.

Alternatively, R ¹ is as defined for the general formula (Xa) or (X), X is a halide of Grignard (Grignard) reagent R ¹ MgX, for example, to run the addition of the acetate using bromide (I) chloride, copper (II) chloride or copper (I) chloride or a copper (II) salt or complex with a catalytic amount of a zinc (II) salt such as zinc ) Or copper (II) acetylacetonate (acac) complex.

The reaction may be carried out in an organic solvent, for example an ether such as THF, 2-methyl THF, methyl tert -butyl ether (TBME), diethyl ether. Surprisingly, the reaction temperature is not particularly critical, and in some cases the reaction can be carried out at low temperatures, for example at about -25 to 0 C, while at higher temperatures up to about 55 C it has been successfully carried out.

(Ia), wherein each R ⁴ is also C (O) OR ¹⁰ , wherein R ¹⁰ is as defined above, but especially H, C _1-6 alkyl, or benzyl, or a compound of formula ) Is particularly suitable for preparing a compound of formula (IVa) or a compound of formula (IV) wherein R < ⁴ > is C (O) OR < ¹⁰ >.

Compounds of formula (IVa) or formula (IV) with different R ⁴ groups can be prepared by methods familiar to those skilled in the art, as described below, from compounds of formula (IVa) or compounds of formula (IV) have.

Representative methods for forming a compound of formula (IVa) or a compound of formula (IV) are described in Example 6, Example 10, and Example 52.

In one embodiment, the compound of formula (IVa) is < RTI ID = 0.0 >

(IVa)

(IVa)

Wherein R < ¹ > is as defined above for a compound of formula (Xa);

Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

In one embodiment, the compound of formula (IVa) is < RTI ID = 0.0 >

(IVa)

(IVa)

Wherein R < ¹ > is as defined above for a compound of formula (Xa);

Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (Ia).

In one embodiment, the compound of formula (IVa) is < RTI ID = 0.0 >

(IVa)

(IVa)

Wherein R ¹ is as defined above for a compound of formula (Xa), and Y, R ² , R ⁴ , and R ⁵ are as defined above for a compound of formula (Ia).

In one embodiment, the compound of formula (IV) is < RTI ID = 0.0 >

(IV)

(IV)

Wherein R < ¹ > is as defined above for a compound of formula (X);

Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (I).

In one embodiment, the compound of formula (IV) is < RTI ID = 0.0 >

(IV)

(IV)

Wherein R < ¹ > is as defined above for a compound of formula (X);

Y, R ² , R ⁴ , and R ⁵ are as defined above for the compound of formula (I).

In one embodiment, the compound of formula (IV) is < RTI ID = 0.0 >

(IV)

(IV)

Wherein R ¹ is as defined above for a compound of formula (X) and Y, R ² , R ⁴ , and R ⁵ are as defined above for a compound of formula (I).

Step (b)

The conversion of a compound of formula (IVa) or of a compound of formula (IV) to a compound of formula (Va) or to a compound of formula (V) can be carried out by hydrogenation, usually catalytic hydrogenation. Suitable catalysts for catalytic hydrogenation include palladium / carbon, palladium / calcium carbonate, palladium / aluminum oxide, platinum / palladium, or Raney nickel catalysts. The reaction may be carried out in an organic solvent, which may be an alcoholic solvent such as methanol, ethanol, or isopropanol; Ethyl acetate; Pyridine; Acetic acid; Cyclopentyl methyl ether (CPME), acetonitrile (MeCN), or N, N -dimethylformamide (DMF). The organic solvent may optionally be mixed with a co-solvent such as acetone or water and / or a base such as triethylamine may also be added.

The choice of catalyst and solvent influences the ratio of the product of formula (Va) or of formula (V) to its isomer of formula (XXXa) or of formula (XXX):

(Va)/(V)

(Va) / (V)

(XXXa)/(XXX).

(XXXa) / (XXX).

More suitably, a palladium / carbon or palladium / calcium carbonate catalyst is used. Typically, the catalyst is present in an amount of 5-10 wt% based on the weight of the matrix (when the matrix is carbon, calcium carbonate, etc.) palladium.

Particularly suitable solvents and catalysts used in the reaction include DMF with a palladium / calcium carbonate catalyst and DMF with a mixture of MeCN and a palladium / carbon catalyst.

Hydrogenation of a compound of formula (IVa) or a compound of formula (IV) will also reduce any alkene bonds in linker Y, if present.

Representative methods for forming compounds of formula (Va) or compounds of formula (V) are described in Examples 7, 11,

Step (c)

The oxidation of a compound of formula (Va) to a compound of formula (VIa) or the oxidation of a compound of formula (V) to a compound of formula (VI) can be carried out using any suitable method . A suitable method is the oxidation of the Dess-Martin periodinan (1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-3- (1H) , Which may suitably be carried out at room temperature in a chlorinated solvent such as chloroform or dichloromethane at a temperature of about 15 to 25 占 폚.

An alternative oxidation method is oxidation using hypochlorite, for example sodium hypochlorite, under acidic conditions provided by, for example, acetic acid. The reaction may be carried out in an aqueous solvent at a temperature of from 0 to 15 캜, more typically from about 0 to 10 캜.

Other oxidation methods include sodium dichromate or, more typically, Jones reaction using chromic trioxide in dilute sulfuric acid. This process is known to be reliable for complete conversion of the bile acid hydroxyl group to the corresponding keto derivative (see Bortolini et al , J. Org. Chem . , 2002 , 67 , 5802). Alternatively, the oxidation can be carried out using TEMPO ((2,2,6,6-tetramethyl-piperidin-1-yl) oxy) or its derivatives.

Representative examples of such processes are described in Example 8, Example 12, and Example 54.

Step (d)

Reduction of a compound of formula (VIa) or of a compound of formula (VI) to form a compound of formula (Xa) or a compound of formula (X), respectively, is typically carried out in a solvent such as a mixture of tetrahydrofuran and water A reducing agent such as sodium borohydride, which is a hydride, which can be used. Typically, the reaction is carried out under basic conditions, for example in the presence of a strong base such as sodium or potassium hydroxide, at a temperature of from about 0 to 110 ° C, more typically from 60 to 100 ° C. Compounds of formula (Xa) wherein R ⁴ is C (O) OH or compounds of formula (X) may be prepared by reduction of compounds wherein R ⁴ is C (O) OH.

This process comprises reacting a compound of general formula (Ia), (IVa), (Va), (VIa), and (Xa) with a compound of general formula (Ia), (IVa), (Va), (VIa) (IV), (V), (VI), and (X) with at least one optional step of converting a compound of formula (I) ), (VI), and (X).

(IVa), (Va), (VIa), and (Xa) or the compounds of formulas (I), (IV), (V) , And (X) to a compound having an alternative Y and / or R ⁴ moiety.

It should be noted that the embodiments described above for different R groups apply equally to the process embodiments just described.

chain  transform

(I), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) The various side chain YR ⁴ groups of the compounds of formula (III) and (IV) - (XI) can be converted to the side chain carboxylic acid, ester, OH, or a reaction involving a protected OH group using, for example, ≪ / RTI > Analogs of the compounds of formulas (Va), (VIa), (V), (VI) and (X) in which the saturated side chain Y ¹ -R ⁴ is converted to the unsaturated side chain YR ⁴ are also prepared as described in more detail below Can be prepared by these methods.

Figure 1 shows the conversion of the compounds of formula (IIa) or of formula (II) in which the side chain is -CH ₂ OH to the other compounds of formula (IIa) or of formula (II), respectively, with different side chains.

This reaction can be carried out in an appropriate case (i.e. chemically rational case) by reacting a compound of formula (Ia), (I), (IIIxa), (IIIx), (IIIya), (IIIy), (IIIxz) IVa) - (XIa), and (IV) - (XI).

As shown in Fig. 1, the compound of formula (IIa) wherein YR ⁴ is CH ₂ -OH or the compound of formula (II) can be prepared from plant sterols such as stigmasterol.

, 또는

를 포함하는 측쇄; 및 또한 -C(O)NHSO₂R¹⁰ 및 -NHC(O)NH-SO₂R¹⁰을 포함하는 카르복실산 유사기를 가진 일반식 (IIa) 또는 일반식 (II)의 화합물로 전환될 수 있다.1, the compound or compounds of the general formula (II) represented by the general formula (IIa) with -CH ₂ OH side chain is, the number X is O or S and alkyl is C _1-6 alkyl, and Et is ethyl the -CH ₂ -9- see bicyclo (3.3.1) _{nonyl, -CH 2 CH 2 CH [B} ( _{alkyl) 2] 2, -CH 2 CN} , -CH 2 CH 2 CN, -CH 2 Br, - _{CH 2 CH [C (O)} OEt] 2, -CH 2 -C≡CH, -CH 2 -CH = CH 2, = CH 2, -C (O) H, -CH 2 NH 2, CH 2 OTBDMS, CH ₂ N ₃ , CH ₂ OMs,

, or

; And also carboxylic acid analogs comprising -C (O) NHSO ₂ R ¹⁰ and -NHC (O) NH-SO ₂ R ^10, to give compounds of formula (IIa) or of formula (II) .

Formula (Ia) with the side chain Y-OH (where Y is -CH ₂ and Y ^2, Y ² is carbon it is at least one as long as more and are as defined for Y as defined above except for short), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) (IV) - the compound (XI) are, by oxidation, for example by suitably using dimethyl sulfoxide and a base, such as oxalyl chloride in the presence of triethylamine, the side chain is -Y ² -C (O) H < / RTI > Alternatively, the oxidation can be carried out using a des-martin puerodienane as shown in Example 27. [

Compounds of general formulas (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) wherein the side chain is -Y ² -C In the compounds of formula (I), (II), (IIIx), (IIIy), and (IV) - (XI), olefination with, for example, compounds of formula (XXII) To provide compounds wherein the side chain is Y ² -CH = CH-Y ³ -C (O) OR ²⁷ :

Ph ₃ P = CH-Y ³ -C (O) OR ²⁷ (XXII)

Wherein Y ³ is a linker Y of the general formula (Ia) and the general formula (IIa) or a linker Y of the general formula (I) and the general formula (II) is a moiety -Y ² -CH ₂ CH ₂ -Y ³ - Is as defined for Y of formula (Ia) and formula (IIa) or for Y of formula (I) and formula (II), except that it may have a shorter carbon chain, Wherein Y ² and Y ³ are as defined for Y, except that they are shorter in length, wherein R ²⁷ is suitably C _1-6 alkyl or benzyl. (EtO) ₂ P (O) CH ₂ Y ³ C (O) OR ²⁷ can also be used.

Olefination can be carried out in a solvent such as dichloromethane at about 15 to 25 占 폚, suitably at room temperature.

These compounds again, 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide (EDCI) by reaction with a coupling agent to the presence of such compounds and, R ⁴ is a carboxylic acid similar to group C (O) and NHSO ₂ R ^10, where R ¹⁰ can be converted to compounds as defined above:

NH ₂ SO ₂ R ¹⁰

Wherein R < ¹⁰ > is as defined above.

Groups of general formula (Ia) OH of the R ⁴ position, (IIa), (IIIxa) , (IIIya), (IIIxz), (IIIyz), and (IVa) - compound and the general formula (XIa) (I), (II), (IIIx), (IIIy), and (IV) - (XI) can be protected with a silyl protecting group. This can be accomplished typically by reaction with (XXIII) as described below in an organic solvent and in the presence of a base such as imidazole or triethylamine. This reaction is shown in Example 22.

X ¹ -Si (R ¹⁶ ) ₃ (XXIII)

Wherein R ¹⁶ is as defined above and X ¹ is a leaving group such as a halide such as chloride or a sulfonate leaving group such as trifluoromethanesulfonate (triflate), methanesulfonate (mesylate) , Or toluene sulfate (tosylate).

R ⁴ is OH in the general formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) compound and formula (I), (II a ), (IIIx), (IIIy), and (IV) - (XI) can also be prepared by the reaction of a sulfonyl halide, such as methanesulfonyl chloride, in the presence of a catalyst such as 4-dimethylaminopyridine To a compound wherein R < ⁴ > is a sulfonate, such as methane sulfonate or toluene sulfonate. This reaction is shown in Example 13. Alternatively, they are a halogenating agent, for example, Example 30 of carbon tetrabromide or Example 35. N, as illustrated in, as illustrated in - by reaction with bromine, such as bromosuccinimide agent, R ⁴ (I), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) , (II), (IIIx), (IIIy), and (IV) - (XI).

Then, such a sulfonate or halide compounds, cyanide salts, such as sodium, or by reaction with potassium cyanide, R ⁴ is cyano general formula (Ia), (IIa), (IIIxa), (IIIya) , (IIIxz), (IIIyz), and (IVa) - (XIa) or to compounds of general formulas (I), (II), (IIIx), (IIIy), and (IV) (See Example 35). Alternatively, the reaction with acetonitrile in the presence of a base such as n -butyllithium may cause a chain elongation reaction such that the side chain -CH ₂ -O-methanesulfonyl or -CH ₂ -Br is branched- CH ₂ CH ₂ -CN. This reaction is shown in Example 33.

Compounds with sulphonate side chains can also be converted to compounds in which R < ⁴ > is nitro by the reaction with nitromethane in the presence of a base such as sodium or potassium carbonate.

Compounds of formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) wherein the side chain is Y ² -C (O) general formula (I), (II), (IIIx), (IIIy), and (IV) - the compound of (XI) is, hunseu dikeo (Hunsdiecker) reaction (a document incorporated herein by both incorporated [J . Org. Chem., 1986, 51, 404-407] and the method disclosed in [VC Edelsztein et al. Tetrahedron, 2009, 65, 3615-3623] reference) and Phl in the presence of copper (II) acetate, using a similar process ( OAc) ₂ , the side chain may be converted to a compound wherein Y ² -CH = CH ₂ . Such compounds with side-chain-Y ² -CH = CH ₂ are again described, for example, in J. Org . Chem ., 1986 , 51 , 404-407 (incorporated herein by reference) to produce a compound wherein the side chain is -Y ² -CH (OH) -CH ₂ -OH . Such a compound can be oxidized to a compound wherein the side chain is Y ² -CH (OH) -C (O) H, which is then reacted with 1,3-propanediol or 1,2-ethanediol in the presence of an acid catalyst such as toluenesulfonic acid Dioxane or 1,3-dioxolane. ≪ / RTI > Similar reactions can be used to produce equivalent cyclic dithioacetals and cyclic amines.

And compound of formula (XIa) (- general formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) with a side chain -Y-CH = CH ₂ The compounds of formula (I), (II), (IIIx), (IIIy) and (IV) - (XI) can also be prepared by hydrogenation, typically on a palladium catalyst, suitably Lindlar catalyst, Lt; RTI ID = 0.0 > -CH = CH, < / RTI >

Compounds of formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) The compounds of formula (II), (IIIx), (IIIy) and (IV) - (XI) can be prepared by reacting an organometallic reagent, for example Li- ≪ / RTI >

Compounds of formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) wherein the side chain --YR ⁴ is --CH ₂ --OH, The compounds of formula (I), (II), (IIIx), (IIIy), and (IV) - (XI) may also be converted into compounds wherein the side chain is = CH ₂ . This can be accomplished by an elimination reaction in which the side chain -YR ⁴ is -CH ₂ -OH is reacted with an acid such as phosphoric acid, sulfuric acid, or toluene sulfonic acid, as shown in FIG. Using a similar reaction can be converted to compounds having a side chain -Y _² -CH ² -OH with a compound having a side chain -Y _² -C = CH ^2. Alternatively, compounds wherein the side chain is = CH ₂ can be prepared by oxidation of -Y ² -CH ₂ -OH to Y ² -CH (O) followed by conversion to an alkene using an olefinization reaction.

Formula with a side chain YC≡CH, = CH _2, or _{^{-Y 2 -C = CH 2 (Ia}} ), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) (XIa) or a compound of general formula (I), (II), (IIIx), (IIIy) and (IV) - (XI) with a borane of formula H-BR ¹⁰ R ¹¹ , May each be -Y-CH ₂ -C (BR ¹⁰ R ¹¹ ) ₂ , -CH ₂ -BR ¹⁰ R ¹¹ , or -Y ² -CH ₂ -BR ¹⁰ R ¹¹ . An example of this reaction is shown in Fig.

(IIIa), (IIIxa), (IIIya), (IIIxz), (IIIyz) and (IIIx) wherein the side chain is -CH ₂ -BR ¹⁰ R ¹¹ or -Y ² -CH ₂ -BR ¹⁰ R ¹¹ (XIa) and a compound of the formula (I), (II), (IIIx), (IIIy), and (IV) - (XI) with phenoxyacetic acid, -CH ₂ -C (O) OH or -Y ² -CH ₂ -C (O) OH.

Of (XIa) - R ⁴ is ^{-CH [C (O) OR 10} ] 2 of the formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) The compounds and compounds of formulas (I), (II), (IIIx), (IIIy), and (IV) - (XI) can be prepared by reacting malonate esters May be prepared from a compound wherein R < ⁴ > is halo, e.g., bromo. This type of reaction is illustrated in Example 32.

R ⁴ is malonate esters ^{-CH [C (O) OR 10} ] 2 of the formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - ( compound and a formula (I) of XIa), (II), ( IIIx), (IIIy), and (IV) - (XI) compound by heating under acidic or basic conditions of the R ⁴ CH ₂ C (O) OH. ≪ / RTI >

Compounds of general formulas (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) ), (II), (IIIx), (IIIy) and (IV) - (XI) can also be obtained by reaction with phosgene to form an acid chloride followed by reaction with diazomethane to give the side chain -YC (O) -CH ₂ -N it can be converted to compound _2.

Diazomethane can be in situ prepared using a conventional method, for example, treatment of N -nitroso- N -methylurea with aqueous sodium or potassium hydroxide in diethyl ether. Suitably, the diazomethane is used in excess, typically in amounts greater than 2 equivalents relative to the acid chloride. The reaction is typically carried out in an organic solvent such as diethyl ether, toluene, or a mixture thereof. The reaction is carried out at a temperature of about -5 to 15 占 폚, typically 0 to 10 占 폚.

Branched -YC (O) is in the presence of an alcohol of the formula at elevated temperature a compound having a -CH ₂ -N ₂ water is treated with silver nitrate to the compound contains, for example,

R ^10a -OH

Wherein R ^10a is as defined for R ¹⁰ in formula (Ia) or formula (I), except that it is not H. Most suitably, R ^10a is C _1-6 alkyl or benzyl. Under these conditions, the compounds undergo Wolff rearrangement and provide a compound whose side chain is -Y-CH ₂ -C (O) OR ^10a , so that the sequence can be used to extend the side chain.

(I), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) wherein the side chain is YC (O) , (IIIx), (IIIy), and (IV) - (XI) can be prepared by reacting the compound of formula By reaction, the side chain can be converted to a compound wherein the side chain is -Y ² -CH ₂ -CN (both of which are incorporated by reference in their entirety, CD Schteingart and AT Hofmann , Journal of Lipid Research, 1988 , 29 , 1387 -1395]; Valentina Sepe et al, Eur. J. Org. Chem., 2012 , 5187-5194).

(Ia), (IIa), (IIb) wherein the side chain is Y ² -C (O) H, wherein Y ² is as defined above for Y except that it is shorter in length by one carbon. (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) the compounds of XI) is a side chain is ^{-Y-CH (XR 10) (} XR 11) , and where Y is -Y _² -CH ² -, for example ^{-Y 2 -CH (OR 10) (} OR 11) , Or -Y ² -CH (SR ¹⁰ ) (SR ¹¹ ), wherein R ¹⁰ and R ¹¹ may be connected together with the atoms to which they are attached to form a cyclic group. This can be accomplished by reacting a compound wherein the side chain is Y ² -C (O) H with a compound of the formula: or a protected version of such a compound wherein the OH or SH group is protected with trimethylsilyl, as shown for example in Example 28 Can:

HX ³ - (CH ₂ ) _p -X ³ H

Wherein X ³ is O, S, or NH and p is 1 to 4, typically 2 or 3.

Compounds of general formulas (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) wherein the side chain is Y ² -C (O) The compounds of formulas (I), (II), (IIIx), (IIIy) and (IV) - (XI) can also be prepared by reaction with a suitable organometallic reagent, typically a Grignard reagent of the formula: _{^{Y 2 -CH (OH) -CH 2}} -CH (oR 10) (oR 11), -Y 2 -CH (OH) -CH 2 -CH (R 10) (oR 11), or -Y ² -CH ( OH) -CH ₂ -CH (SR ¹⁰ ) (SR ¹¹ ):

XMg-CH ₂ -R ^4c

Wherein X is halo, typically bromo, and R ^4c is -CH (OR ¹⁰ ) (OR ¹¹ ), -CH (R ¹⁰ ) (OR ¹¹ ), or CH (SR ¹⁰ ) (SR ¹¹ ).

Of formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz) side chain is _{^{-Y 2 -CH (OH) -CH 2}} -CH (OR 10) (OR 11), And the compounds of formulas (IVa) - (XIa) or the compounds of formulas (I), (II), (IIIx), (IIIy) and (IV) - (XI) Y ² -CH = CH-C (O) H. The aldehyde may then be oxidized to provide the carboxylic acid and / or the alkylene linkage may be reduced by hydrogenation to provide a saturated side chain wherein Y is -Y ² -CH ₂ CH ₂ -.

R ⁴ is -N ₃ in the general formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - Compounds of formula (XIa) (I), (II), (IIIx), (IIIy), and (IV) - (XI) compound, a leaving group, such that each R ^4, and toluene sulfonate, methane sulfonate (Ia) of, (IIa), (IIIxa) , (IIIya), and (IVa) - (XIa) of the compound or the general formula (I), (II), (IIIx), (IIIy), and (IV) - the compound of (XI), or R ⁴ is halo (IIIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IIIx), which are sulfonyl esters such as toluene sulfonate or methane sulfonate, Can be prepared from the compound of formula IVa) - (XIa) or a compound of formula (I), (II), (IIIx), (IIIy), and (IV) - (XI) have. This is illustrated in Example 34.

R ⁴ is NH ₂ in the general formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - the compound or general formula (XIa) (I), ( II), (IIIx), ( IIIy), (IIIxz), (IIIyz), and (IV) -, each R ⁴ is an azide of the general formula as illustrated in example 34 compound of (XI) ( (I), (IIa), (IIIxa), (IIIya), and (IVa) - (XIa) Lt; RTI ID = 0.0 > XI). ≪ / RTI >

R ⁴ is -NHC (O) NHSO ₂ R ¹⁰ in the general formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - compound of (XIa) or to the presence of a reagent such as carbonyldiimidazole (CDI) - general formula (I), (II), (IIIx), (IIIy), and (IV) - compound of (XI) N, N ' by using the coupling reaction with the compound of formula, R ⁴ may be prepared from a compound NH _2:

NH ₂ SO ₂ R ¹⁰

Wherein R < ¹⁰ > is as defined above.

(IIIa), (IIIxz), (IIIyz), and (IVa) - (XIa) wherein R ⁴ is tetrazol-5-yl or a compound of the formula The compound of formula (II), (IIIx), (IIIy), and (IV) - (XI) can be prepared from azidomethylsilane / dibutylstannanone or Bu ₃ SnN ₃ as described in US2016 / 0145295 (IIIa), (IIIxz), (IIIyz), and (IV) - (XI) wherein R ⁴ is CN, or a compound represented by the general formula (I), (II), (IIIx), (IIIy), and (IV) - (XI). Alternatively, a compound wherein R < ⁴ > is CN may be reacted with sodium azide in the presence of an acid. For example, the toluene / DMF of NaN ₃ / NH ₄ Cl (literature [Organic and Biomolecular Chemistry, 2008, 6, 4108]) or in DMF NaN ₃ / NEt ₃ .HCl (literature [Brown et al .; Bioorg Med Chem Lett , 2002 , 12 , 3171). Alternatively, R ⁴ is azide by the cyanide compounds suitable for the compound under reductive conditions, for example reaction with tosyl cyanide, R ⁴ may provide a tetrazol-1-yl.

R ⁴ is an amino-tetrahydro sol general formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - the compound or general formula (XIa) (I), ( Compounds of formula (II), (IIIx), (IIIy), and (IV) - (XI) may be prepared from compounds wherein the group at the R ⁴ position is a mesyl by reaction with a 5-aminotetrazole.

Compounds of general formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) wherein the side chain is -Y ² -C The compounds of formulas (I), (II), (IIIx), (IIIy), and (IV) - (XI) may also be prepared by reacting a hydride, borohydride or cyanoborohydride Y ² -CH ₂ -NR ¹⁰ R ¹¹ by reductive amination with an amine of the following formula and a reducing agent such as sodium hydride, sodium hydride or sodium cyanoborohydride,

H-NR ¹⁰ R ¹¹

Wherein R < ¹⁰ > and R < ¹¹ > are as defined above.

(IIIa), (IIIxz), (IIIyz), and (IVa) - (XIa), wherein R ⁴ is C (O) OR ¹⁰ , I), (II), ( IIIx), (IIIy), and (IV) - (XI) compound, R ⁴ is ^{OC (O) R 10, C} (O) NR 10 R 11, OR 10, OSi of _{^{(R 13) 3, S (}} O) R 10, SO 2 R 10, OSO 2 R 10, SO 3 R 10, OSO 3 R 10, halo, CN, C (O) R 10, CH (OR 10) ( ^{OR 11), CH (R 10} ) (OR 11), CH (SR 10) (SR 11), NR 10 R 11, BR 10 R 11, C (O) CH 2 N 2, -CH = CH 2, - May be converted to compounds of the same general formula, such as C≡CH, CH [C (O) OR ¹⁰ ] ₂ or CH (BR ¹⁰ R ¹¹ ) ₂ , an azide, or a carboxylic acid analogue such as a tetrazole.

The general formula R ⁴ are ^{_{SO 3 R 10 (Ia),}} (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - the compound or general formula (XIa) (I) (II), (IIIx), (IIIy), and (IV) - (XI) are disclosed in WO2008 / 002573, WO2010 / 014836, and WO2014 / 066819, , R < ⁴ > is C (O) OH.

Therefore, a compound of the general formulas (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - (XIa) wherein R ⁴ is C (I), (II), (IIIx), (IIIy) and (IV) - (XI) are first reacted with C _1-6 alkanoyl or benzoyl chloride, or C _1-6 alkanoic anhydride, OH groups can be protected. Then, to reduce the carboxylic acid group to OH, the protected compound can be reacted with a hydride, suitably lithium aluminum hydride or a reducing agent such as sodium borohydride. Classon et al. , J. Org. Chem. , 1988 , 53 , 6126-6130], which is incorporated herein by reference, the alcohol group may be replaced by a halogen, such as bromine or iodine, using a triphenylphosphine / imidazole / halogen method. The halogenated compound can then be reacted with sodium sulfite in an alcoholic solvent to provide a compound having an SO ₃ ^- Na ⁺ substituent.

R ⁴ is OSO ₃ R ¹⁰ (I), (IIa), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz) , (IIIy), and (IV) - (XI) can be prepared by reacting the alcohol from the step of reducing the protected carboxylic acid as described above with chlorosulfonic acid in the presence of a base such as triethylamine to form protected To obtain a triethylamine salt. The base hydrolysis as described above can be used to remove the protecting group. (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz) wherein R ⁴ is OSO ₂ R ¹⁰ from the reaction of the alcohol and sulfonyl chloride, , And (IVa) - (XIa) or the compounds of the formulas (I), (II), (IIIx), (IIIy), and (IV) - (XI).

Compound or general (XIa) - R ⁴ is C (O) NR ¹⁰ R ¹¹ in general formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) Compounds of formula (I), (II), (IIIx), (IIIy), and (IV) - (XI) may be prepared by reaction of an amine of formula H-NR ¹⁰ R ^{11 with} heating in a suitable solvent , ≪ / RTI > carboxylic acids. Compounds of the general formula (Ia), (IIa), (IIIxa), (IIIya), and (IVa) - (XIa) wherein R ⁴ is C (O) NR ¹⁰ R ¹¹ or OSO ₃ R ¹⁰ , Compounds of formula (II), (IIIx), (IIIy), (IIIxz), (IIIyz), and (IV) - (XI) are also described in Festa et al. , J. Med. Chem. , 2014 , 57 , ≪ / RTI > 8477-8495) (incorporated herein by reference).

Examples thereof are iso-from-butyl chloroformate and the coupling reagent and triethylamine, respectively taurine or glycine and, R ⁴ is C (O) by reacting OH, a compound of the same formula in the presence of a base such as R ⁴ is _{C (O) NH (CH 2} ) 2 SO 3 H or _{C (O) NHCH 2 CO 2} H in the general formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz) , (IVa) - (XIa), or a compound of the general formulas (I), (II), (IIIx), (IIIy), (IV) - (XI) or a salt thereof.

R ⁴ is C (O) R ¹⁰ in the general formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - the compound or general formula (XIa) ( I), (II), ( IIIx), (IIIy), and (IV) - (XI) compound, R ⁴ is C (O using diisobutylaluminum hydride (DIBAL-H) of one equivalent of (For example, see WO2011 / 014661, which is hereby incorporated by reference) to obtain an aldehyde of formula (I) wherein R < ⁴ > is C (O) OR < ¹⁰ >.

Alternatively, the aldehyde may be prepared by oxidation of the protected compound wherein R < ⁴ > is OH, as described above. Oxidation can be swern oxidation, which is carried out using oxalyl chloride and dimethylsulfoxide followed by triethylamine (see, for example, Xiang-Dong Zhou et al , Tetrahedron , 2002 , 58 , 10293-10299). Alternatively, the compounds described in Carnell et al., J. Med. Chem. , 2007 , 50 , 2700-2707, the oxidation can be carried out using an oxidizing agent such as pyridinium chlorochromate (PCC).

And R ⁴ is C (O) R ^10, where R ¹⁰ is the formula other than hydrogen (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) - compound or formula (I), (II), (IIIx), (IIIy) of (XIa), and (IV) - (XI) compounds by known methods, for example, R ⁴ is C (O) H aldehyde with a suitable Grignard reagent followed by oxidation. Such methods are well known to those skilled in the art.

The other R ⁴ formula (Ia), (IIa), (IIIxa), (IIIya), (IIIxz), (IIIyz), and (IVa) with a group - a compound or general formula (XIa) (I), ( II ), (IIIx), (IIIy), and (IV) - (XI) may be prepared from such compounds of the same general formula by methods familiar to those skilled in the art.

General information

The present invention will now be described in more detail with reference to examples.

In the examples, the following abbreviations were used:

Example

General procedure

Example  1 and Example  2-epoxidation reaction

Example  1-acetone / H ₂ O TCCA  using ( 6β , 7β , 22 E ) -6,7-epoxy-3-oxo-4,22-colladiene-24-oic acid ethyl ester (IA)

( 6β , 7α , 22 E ) -7- Chloro -6- Hydroxy -3-oxo-4,22- Cola dien -24-oxo-ethyl ester ( IIIxA ) or ( 6α , 7β , 22 E ) -6- Chloro -7- Hydroxy Oxo-4,22-colladiene-24-oic acid ethyl ester) (IIIyA)

(22E) -3-oxo-4,6,22-collatriene-24-oic acid ethyl ester (2.0 g, 5.0 mmol, patent application no. PCT / GB2015 / 053516; , As obtained from stigmasterol, as described above) was dissolved in acetone: H ₂ O (12: 1, 15 vol). TCCA (0.47 g, 0.4 eq) was added as a single portion and the solution was stirred for 1.5 h. The resulting mixture was filtered, diluted with CH ₂ Cl _2, and washed with 10% aqueous NaHSO ₃ (25 mL) followed by H ₂ O (25 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give (6β, 7α, 22E) -7-chloro-6-hydroxy-3-oxo-4,22-colladiene- (IIIaA) (0.89 g, 2.0 mmol) was added to a solution of the ester (IIIxA) or (6.alpha., 7.beta., 22E) -7-hydroxy-6-chloro-3- As a solid.

^{1 H NMR (400 MHz, CDCl} 3): δ = 6.8 (1H, dd, J = 15.6, 9.0, C22H), 5.88 (1H, s, C4H), 5.74 (1H, d, J = 15.6, C23H), 4.35 (1H, d, J = 3.0, C6H), 4.19-4.14 (3H, m, OC H 2 CH 3 + C7H), 2.54-1.08 (27H, m), 0.79 (3H, s, CH 3).

¹³ C NMR (100 MHz, CDCl ₃ ):? = 199.9, 197.1, 164.7, 154.3, 129.4, 119.2, 77.1, 63.9, 60.2, 54.8, 50.9, 44.5, 42.7, 39.6, 38.9, 37.8, 36.8, 34.2, 34.0 , 27.9, 23.1, 20.6, 20.3, 19.2, 14.3, 12.3.

HRMS (ESI-TOF) m / z : (M + H) ⁺ 449.2453 calculated for C ₂₆ H ₃₈ Cl ₁ O ₄ ; Measurement: 449.2425;

( 6β , 7β , 22 E ) -6,7-epoxy-3-oxo-4,22- Cola dien -24-oxo-ethyl ester (IA)

(6?, 7 ?, 22E) -7-hydroxy-3-oxo-4,22-colladiene-24-oic acid ethyl ester (IIIxa) (IIIa) (0.89 g, 2.0 mmol) was dissolved in CH ₂ Cl ₂ (10 mL) and DBU (0.45 mL, 1.5 eq) was added to a solution of 6- Was added. The solution was stirred for 18 h before additional DBU (0.15 mL, 0.5 eq) was added. After stirring for an additional 4.5 h, DBU (0.15 mL, 0.5 eq) was added and the solution was stirred for 19 h. The solution was concentrated to dryness to provide the title compound (0.40 g, 1.0 mmol) as a off-white solid after column chromatography.

^{1 H NMR (400 MHz, CDCl} 3): δ = 6.8 (1H, dd, J = 15.6, 9.0, C22H), 6.13 (1H, s, C4H), 5.74 (1H, d, J = 15.6, C23H), 4.17 (2H, q, J = 7.1, OC H 2 CH 3), 3.35-3.33 (2H, m, C6H and C7H), 2.63-2.53 (1H, m ), 2.43-2.24 (2H, m), 2.02- 1.03 (23H, m), 0.76 (3H, s, CH 3).

¹³ C NMR (100 MHz, CDCl ₃ ):? = 198.2, 166.9, 163.0, 154.0, 129.3, 119.4, 60.2, 59.1, 55.7, 54.7, 52.6, 51.6, 43.7, 39.6, 39.2, 36.6, 36.1, 35.5, 34.1 , 28.0, 23.8, 21.3, 19.2, 16.8, 14.3, 12.1.

HRMS (ESI-TOF) m / z : (M + H) < ⁺ > calculated for C ₂₆ H ₃₇ O ₄ ⁺ 413.2686; Measurement: 413.2691.

Example  2-acetic acid TCCA  using ( 6β , 7β , 22 E ) -6,7-epoxy-3-oxo-4,22-colladiene-24-oic acid ethyl ester

( 6β , 7α , 22E) -6- Acetoxy -7- Chloro -3-oxo-4,22- Cola dien -24-oxo-ethyl ester

(22 E ) -3-oxo-4,6,22-collatriene-24-oic acid ethyl ester (1.0 g, 2.5 mmol) was dissolved in AcOH (10 mL). TCCA (235 mg) was added as a single portion and the solution was stirred for 18 h. The mixture was diluted with EtOAc (100 mL) and washed with 5% aqueous NaHSO ₃ (100 mL) followed by H ₂ O (2 × 50 mL) and 5% aqueous NaHCO ₃ (50 mL). The organic layer was dried over Na ₂ SO _4, filtered, and concentrated in vacuo. (6β, 7α, 22E) -6- acetoxy-7-chloro-3-oxo -4,22- coke diene -24- Osan ethyl ester (454 mg, yellow oil) was subjected to column chromatography (SiO _2, heptane: EtOAc < / RTI > gradient).

^{1 H NMR (400 MHz, CDCl} 3): δ = 6.81 (1H, dd, J 15.6, 9.0, C22H), 6.02 (1H, s, C4H), 5.75 (1H, dd, J 0.7, 15.6, C23H), 5.42 (1H, d, J 3.0 , C6H), 4.15 (2H, dd, J 7.1, 14.2, OC H 2 CH 3), 4.11 (1H, app. t, J 2.8, C7H), 2.55-2.25 (3H, m), 2.14-2.00 (3H, m ), 2.07 (3H, s, OAc) .1.87-1.11 (17H, m), 1.11 (3H, d, J 6.8, C21H 3), 0.81 (3H, s, CH ₃ ) (see Fig. 2).

^{13 C NMR (100 MHz, CDCl} 3): δ = 198.9 (C = O), 168.7 (C = O), 166.9 (C = O), 158.4 (C5), 154.0 (C22H), 131.9 (C4H), 119.3 (CH ₃ ), 76.5 (C 6 H), 61.2 (C 7 H), 60.1 ( CH ₂ CH ₃ ), 54.7 (CH ₃ ), 50.8 _{2), 37.6 (C),} 36.8 (CH 2), 35.0 (CH), 34.1 (CH 2), 27.8 (CH 2), 23.1 (CH 2), 21.1 (CH 3 C (O)), 20.5 (CH ₂ ), 19.5 ( CH ₃ CH ₂ ), 19.2 (C ₂₁ H ₂ ), 14.3 (CH ₃ ), 12.4 (CH ₃ ) (see FIG.

( 6β , 7β , 22 E ) -6,7-epoxy-3-oxo-4,22- Cola dien -24-oxo-ethyl ester

(48 mg) was dissolved in EtOH (5 mL) and K ₂ CO ₃ (5 mL) was added dropwise to a solution of (6β, 7α, 22E) -6-acetoxy- (32 mg). The mixture was stirred at reflux for 4 h, then filtered and concentrated in vacuo to give the desired unreacted? -Epoxide in quantitative yield. The identity of the product was confirmed by ¹ H NMR and TLC comparison with the data obtained for compound (IA) prepared according to Example 1.

Example  3-formic acid TCCA  using ( 6β , 7β , 22 E ) -6,7-epoxy-3-oxo-4,22-colladiene-24-oic acid ethyl ester (IA)

(22 E ) -3-oxo-4,6,22-collatriene-24-oic acid ethyl ester (1.0 g, 2.5 mmol) was dissolved in formic acid (10 mL). TCCA (235 mg) was added as a single portion and the solution was stirred for 15 min. The mixture was diluted with EtOAc (100 mL) and washed with 5% aqueous NaHSO ₃ (100 mL) followed by H ₂ O (2 × 50 mL). The organic layer was dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The residue was dissolved in EtOH (10 mL) and K ₂ CO ₃ (698 mg, 5.05 mmol) was added. The mixture was stirred at 65 < 0 > C for 3 h and then concentrated in vacuo. Column chromatography, which was purified by (SiO _2, heptane eluting with EtOAc gradient) to object (6β, 7β, 22 E) -6,7- epoxy-3-oxo -4,22- coke diene -24- Osan Ethyl ester (330 mg) as an off-white solid. The identity of the product was confirmed by ¹ H NMR and TLC comparison with the data obtained for compound (IA) prepared according to Example 1.

Example  4-acetone / H ₂ O DBDMH  Using (22 E ) -6,7-epoxy-3-oxo-4,22-colladiene-24-oic acid ethyl ester (6β, 7β) and (6α, 7α)

A solution of (22 E ) -3-oxo-4,6,22-collatriene-24-oic acid ethyl ester (396 mg, 1.0 mmol) in acetone: H ₂ O (9: Benzoic acid (61 mg, 0.5 mmol) followed by 1,3-dibromo-5,5-dimethylhydantoin (286 mg, 1 mmol) was added and the solution was stirred for 2 h. The mixture was diluted with EtOAc (50 mL) and washed with 5% aqueous NaHSO ₃ (10 mL) and water (2 x 25 mL). The organic layer was dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The resulting yellow oil was dissolved in CH ₂ Cl ₂ (8 mL), DBU (0.5 mL) was added and the solution was stirred for 16 h. The mixture was concentrated and the residue (dark brown oil) to column chromatography to yield the (SiO _2, heptane eluting with EtOAc gradient) (22 E) -6,7- epoxy-3-oxo -4,22- (See Fig. 4, based on the integral of the characteristic protons of CH4 in ¹ H NMR) as a 2: 1 mixture of ( ⁶ ?, 7?) Versus (137 mg, 0.33 mmol) in 33% yield. The stagnation of the product in the mixture was confirmed by < ¹ > H NMR and compared to the data obtained for compound (IA) prepared according to Example 1 and its 6.7 alpha-epoxy isomer, as described by Uekawa et al. in Biosci . Biotechnol . Biochem . 2004 , 68 , 1332-1337] and synthesized XXX.

Example  5-acetone / H ₂ O DBDMH  The 6,7-epoxy-3-oxo-4,22- Cola Synthesis of (6β, 7β) and (6α, 7α) mixture of dien-24-oic acid ethyl ester

_{Acetone: H 2 O (12: 1} , 5 mL) of (20 S) -20- acetoxymethyl-phe regeuna 4,6-diene-3-one at ambient temperature to a solution of (370 mg, 1.00 mmol) 1,3-dibromo-5,5-dimethylhydantoin (229 mg, 0.80 mmol) was added in one portion and the solution was stirred for 1 h. An additional portion of 1,3-dibromo-5,5-dimethylhydantoin was added (40 mg, 0.14 mmol) and after 10 min the mixture was diluted with EtOAc (50 mL) and washed with 5% aqueous NaHSO ₃ (25 mL) and 5% aqueous NaHCO ₃ (25 mL). The organic phase was dried over anhydrous Na ₂ SO _4, filtered, and concentrated in vacuo. Purification by: (eluting with EtOAc gradient SiO _2, heptane), 1.2 of bromide gave the parent high: The residue was purified by column chromatography to give a 1: 1 mixture (102 mg, 0.22 mmol) (ratio characteristic in the ¹ H NMR Lt; / RTI > peak).

^{1 H NMR (400 MHz, CDCl} 3): δ = 5.95 (1H, s, C4H (a)), 5.86 (1.2H, s, C4H (b)), 4.59 (1H, d, J 2.6, C6H (a )), 4.47 (1.2H, d , J 2.8, C6H (b)), 4.30 (1.2H, app. t, J 2.7, C7H (b)), 4.10-4.04 (2.2H, m, C H A H _{B OAc), 4.04 (1H,} app. t, J 2.2, C7H (a)), 3.82-3.76 (2.2H, m, CH A H B OAc), 3.13 (1.2H, br. s, OH (a) ), 2.75 (1H, br. s, OH (b)), 2.60-1.02 (2.2H, m), 2.54-1.08 (57.2H, m), 0.80 (6.6H, s, CH 3).

The isolated mixture of bromohydrin (72 mg, 0.15 mmol) was dissolved in CH ₂ Cl ₂ (3 mL), DBU (50 μL) was added and the solution was stirred for 18 h. It is concentrated and the residue and the mixture in vacuo column chromatography to yield the (SiO _2, heptane eluting with EtOAc gradient) (6β, 7β) 1.2 vs. (6α, 7α) Epoxide: 1 mixture in quantitative yield (59 mg, 0.15 mmol).

Example  6- Example  9 - ( 6α , 5β ) -3,7- Dioxo -6-ethyl-cholan-24-oic acid ( VIAA ) ( Obeticolic acid (OCA)  Synthesis of a precursor for

Example  6 - ( 6α , 7β , 22 E ) -6-ethyl-7- Hydroxy -3-oxo-4,22- Cola dien -24-oxo-ethyl ester ( IVA ) Synthesis of

To the solution of ZnCl ₂ in THF (0.7 M, 31.2 mL, 21.8 mmol, 0.9 eq) was added anhydrous THF (40 mL) and the contents were cooled to -10 ° C. A solution of EtMgBr in THF (1.0 M, 43.5 mL, 43.5 mmol, 1.8 eq) was added over 25 min. Solid CuCl (240 mg, 2.6 mmol, 0.1 eq) (6β, 7β, 22 E) in addition to the one full minute, and THF (40 mL) -6,7- epoxy-3-oxo-Cola -4,22- Dien-24-oic acid ethyl ester (IA) (10 g, 24.2 mmol) was added dropwise over 15 min. The reaction mixture was stirred for 1 h at -10 <0> C (TLC 1: 1 heptane: EtOAc, visualized by UV and developed using Ceric Ammonium Molybdate Stain) and added dropwise to a saturated aqueous NH ₄ Cl (80 mL) . &Lt; / RTI &gt; The inorganic salts were filtered off, rinsed with TBME (100 ml), and the filtrate was separated. The organic phase was washed with saturated aqueous NH ₄ Cl (80 mL) and 10% aqueous NaCl (80 mL). The organic phase was dried over Na ₂ SO _4, filtered, and concentrated in vacuo at 40 ℃. Column chromatography to yield the (SiO _2, 0-50% EtOAc-heptane) to provide the title compound as a colorless oil which solidified upon standing (9.6 g, 90% yield).

^{1 H NMR (400 MHz, CDCl} 3): δ = 6.82 (1H, dd, J = 15.6, 9.0, C22H), 5.84 (1H, d, J = 1.6, C4H), 5.74 (1H, d, J = 15.6 , C23H), 4.17 (2H, q, J = 7.1, OC H 2 CH 3), 3.13 (1H, t, J = 9.7 C7H), 2.42-2.23 ( 4H, m), 2.05-0.89 (26H, m), 0.91 (3H, t, J = 7.4, CH 3), 0.77 (3H, s, CH 3).

¹³ C NMR (100 MHz, CDCl ₃ ):? = 119.6, 169.1, 167.0, 154.2, 122.8, 119.3, 77.6, 60.2, 55.3, 54.1, 49.8, 48.2, 43.9, 43.1, 39.5, 39.4, 38.6, , 28.5, 26.9, 21.5, 19.4, 18.9, 18.8, 14.3, 12.4, 10.7.

(IR) v _max (cm ^-1 ): 3473, 2937, 1716, 1650, 1606.

HRMS (ESI-TOF) m / z: C 28 H 43 O 4 The (M + H) ⁺ calculated for 443.3161; Measurement: 443.3155.

Example  7 - ( 5β , 6α 7β ) -6-ethyl-7- Hydroxy -3-oxo-cholan-24-oic acid ethyl ester (VA)

Under an argon atmosphere in a round bottom flask followed by DMF (25 mL) to _{5% Pd / CaCO 3 (1.2} g) (6α, 7β, 22 E) -6- ethyl-7-hydroxy-3-oxo -4,22 -Colladiene-24-oic acid ethyl ester (IVA) (5.6 g). The mixture was cooled to -10 DEG C and the flask was evacuated and charged with hydrogen 3 times with vigorous stirring. After stirring the mixture for 48 h (IPC by TLC, eluent 1: 1 EtOAc: heptane; visualized by anisaldehyde staining) under a hydrogen atmosphere keeping the temperature at -10 &lt; 0 &gt; C, the flask was evacuated and charged with argon Filter and wash the catalyst with TBME (100 mL). The filtrate was washed with 10% aqueous NaCl (3 x 50 mL), dried, filtered over Na ₂ SO _4, and concentrated in vacuo at 40 ℃. Column chromatography to yield the (SiO _2, 2-30% heptane EtOAc) (5β, 6α, 7β ) -6- ethyl-7-hydroxy-3-oxo-kolran -24- Osan ethyl ester (VA) Was obtained in 89% yield (4.5 g).

^{1 H NMR (400 MHz, CDCl} 3): δ = 4.12 (2H, q, J = 7.1, OC H 2 CH 3), 3.23 (1H, app t, J = 8.4 C7H.), 2.38-0.93 (37H, m), 0.85 (3H, t , J = 4.7, CH 3), 0.71 (3H, s).

^{13 C NMR (100 MHz, CDCl} 3): δ = 212.0, 174.2, 75.1, 60.2, 56.0, 55.0, 45.2, 44.0, 43.7, 43.6, 40.1, 39.6, 37.7, 37.0, 36.6, 35.2, 34.7, 31.3, 31.0 , 28.5, 26.8, 22.8, 21.9, 20.7, 18.4, 14.3, 12.2, 11.1.

Example  8 - ( 5β , 6α , 3,7- Dioxo -6-ethyl-cholan-24-oic acid ethyl ester (VIA)

To a solution of (5β, 6α, 7β) -6-ethyl-7-hydroxy-3-oxo-cholan-24-oic acid ethyl ester (VA) (2.4 g) in DMF (7 ml) and CH ₃ CN To the solution was added NaBr (111 mg) followed by AcOH (4.8 mL) and the mixture was cooled to 5 &lt; 0 &gt; C. A solution of sodium hypochlorite (~ 13% w / v, 4.5 mL) was added dropwise over 15 min and the mixture was stirred for 1 h at 5 &lt; 0 &gt; C. As gomilhwa mixture was added to additional CH ₃ CN (20 mL) at which point the cooling bath was removed. The mixture was allowed to stir at ambient temperature for 1 h and then sodium hypochlorite (~13% w / v, 3 mL) was added dropwise after the addition of a further amount of AcOH (3 mL). The reaction mixture was stirred for 2 h at ambient temperature and a vigorously stirred solution of aqueous 5% w / v Na ₂ SO ₃ (360 mL) was added, followed by the addition of EtOAc (150 mL). The phases were separated and the organic phase was washed with 5% aq. NaHCO ₃ (3 x 100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Column chromatography to yield the (SiO _2, 0-50% EtOAc-heptane) to give the title compound in 77% yield (1.84 g) as a colorless oil.

^{1 H NMR (400 MHz, CDCl} 3): δ = 4.09 (2H, q, J = 7.1, OC H 2 CH 3), 2.73-2.69 (1H, m), 2.44 (1H, t, J = 11.3), 2.35-0.88 (34H, m), 0.78 (3H, t, J = 7.4), 0.67 (3H, s).

^{13 C NMR (100 MHz, CDCl} 3): δ = 212.0, 210.5, 174.2, 60.2, 54.9, 52.4, 52.3, 50.0, 48.9, 43.7, 42.6, 38.9, 38.3, 36.7, 35.9, 35.5, 35.2, 31.3, 31.0 , 28.2, 24.6, 22.9, 22.3, 18.6, 18.4, 14.2, 12.1, 11.8.

Example  9 - ( 5β , 6α ) -3,7- Dioxo -6-ethyl-cholan-24-oic acid ( VIAA ) ( Obeticolic acid (OCA)  Synthesis of a precursor for

(VIA) (0.5 g) was dissolved in IPA (8 mL), 0.5 M aqueous NaOH (3 mL) was added and the mixture was stirred at room temperature for 3 hours. Respectively. The mixture was stirred at 60 &lt; 0 &gt; C for 2 h. After removal of IPA at 60 &lt; 0 &gt; C under vacuum, 2 M HCl (10 mL) followed by EtOAc (50 mL) with vigorous stirring. The phases were separated and the organic phase was washed with brine (2 x 25 mL) and concentrated in vacuo to give the title compound (468 mg) in quantitative yield. The obtained material (6α, 7α, 22 E) -6,7- epoxy-3-oxo-diene -24- -4,22- coke was the same as that synthesized by a similar route from Osan ethyl ester (IVB) ⁽¹ H And ¹³ C NMR, TLC, and HPLC) (see Figures 5 and 6).

Example  10- Example  19 - ( 3α , 5β , 6α , 7α ) -6-ethyl-3,7- Dihydroxy -Cholan-24-oic acid (OCA)

Example  10 - ( 6α , 7β , 20 S ) -20- Acetoxymethyl -6-ethyl-7- Hydroxy - Preg N-4-en-3-one

A solution of THF (14 mL) and ZnCl ₂ (13 mL, 0.5 M solution, 6.5 mmol in THF) was cooled to -15 ℃. Ethylmagnesium bromide (13 mL, 1 M solution in TBME, 13 mmol) was added dropwise over 25 min. Copper (I) chloride (72 mg, 0.72 mmoL) was added and the mixture was stirred at -15 C for 10 min. (20 S) -20- acetoxymethyl β- -6,7-epoxy-4-en-3-on-profile regeuna (2.8 g, 7.24 mmol) over a 30 min the organic was dissolved in THF (11 mL) Lt; / RTI &gt; The mixture was stirred at -15 &lt; 0 &gt; C for 1 h. Ethylmagnesium bromide (13 mL, 1 M solution in TBME, 13 mmol) was added dropwise over 30 min and the reaction mixture was stirred for 30 min. Ethylmagnesium bromide (7.5 mL, 1 M solution in TBME, 7.24 mmol) was added dropwise over 30 min and the reaction mixture was stirred for an additional 30 min. Copper ( I) chloride (78 mg, 0.78 mmol) was added and the mixture was stirred at -15 <0> C for 40 min. An ammonium chloride solution (5 mL of a saturated aqueous solution) was added dropwise and the temperature allowed to warm to 2 &lt; 0 &gt; C. The mixture was filtered and the filter cake was washed with TBME (80 mL). The filtrate was washed with ammonium chloride (3 x 50 mL saturated aqueous) and sodium chloride (50 mL, 5% aq.). The organic phase was concentrated in vacuo (6α, 7β, 20 S) -20- acetoxy-6-ethyl-7-hydroxy-4-profile regeuna yen and provided the 3-one (3.0 g) as a yellow syrup , Which was used without further purification.

Example  11 - ( 5β , 6α , 7β , 20 S ) -20- Acetoxymethyl -6-ethyl-7- Hydroxy Synthesis of pregna-3-one

Unrefined (6?, 7?, 20S) -20-acetoxymethyl-6-ethyl-7-hydroxy-pregna-4-en-3-one (0.95 g, 2.4 mmol) was dissolved in DMF and the vessel was purged with argon. Pd / CaCO3₃(210 mg) was added and the mixture was cooled to -15 &lt; 0 &gt; C. The mixture was degassed and charged with hydrogen three times. The reaction mixture was stirred at -15 [deg.] C for 1 h and allowed to warm to 18 [deg.] C. After 4 h at 18 &lt; 0 &gt; C the mixture was filtered (0.2 [mu] m PTFE filter) and the filter cake was washed with DMF (4 mL). The filtrate was poured into water (50 mL) and extracted with TBME (50 mL). The aqueous phase was re-extracted with TBME (3 x 50 mL) and the combined organic layers were washed with sodium chloride (25 mL, 5% aqueous) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (heptane-EtOAc) to give (5β, 6α, 7β, 20S) -20-acetoxymethyl-6-ethyl-7-hydroxy-pregna-3-one (0.29 g, 28% yield over 2 steps), R_f: 0.46 (1: 1, heptane: EtOAc);^One&Lt; 1 &gt; H NMR (700 MHz, CDCl3₃): delta = 4.08 (1H, dd,J10.7, 3.4), 3.79 (1H, dd,J10.7, 7.5), 3.23 (1H, t,J9.7), 2.30 (1H, td,J(2H, m), 2.05 (3H, s), 1.91-1.80 (4H, m), 1.75-2.23 M), 1.03 (3H, s), 1.03 (3H, d), 1.51 (6H, m), 1.47-1.36J6.6), 0.85 (3H, t,J7.5), 0.74 (3H, s);¹³C &lt; / RTI &gt; NMR (176 MHz, CDCl3₃):? = 212.1 (C-3), 171.4 (OC = O), 75.0, 69.5, 55.7, 51.9, 45.1, 44.1, 43.7, 43.6, 39.9, 39.5, 37.6, 37.0, 36.6, 35.7, 34.8, 28.1, 26.9, 22.8, 21.9, 21.0, 20.7, 17.2, 12.3, 11.1.

Example  12 - ( 5β , 6α , 20 S ) -20- Acetoxymethyl -6-ethyl- Pregnana -3,7- Dion's  synthesis

(5β, 6α, 7β, 20 S) -20- acetoxy-6-ethyl-7-hydroxy-phe regeuna 3-one (197 mg, 0.47 mmol) was dissolved in CH ₂ Cl ₂ (5 mL) And Dess-Martin periodinane (DMP, 240 mg, 0.56 mmol) was added. The mixture was stirred at 18 [deg.] C. After 1 h 40 min, a second portion of DMP (124 mg, 0.29 mmol) was added. After 2 h 35 min, a third portion of DMP (60 mg, 0.14 mmol) was added. After 2 h 50 min, the mixture was quenched with sodium thiosulfate / sodium bicarbonate solution (15 mL of 10% thiosulfate / 2% bicarbonate solution) and stirred until a negative starch / iodide test was obtained Respectively. The phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 x 5 mL). The combined organic phases were washed with sodium chloride (5 mL of 5% aqueous solution) and concentrated. The residue was purified by flash chromatography (EtOAc- heptane) on silica gel (5β, 6α, 20 S) -20- acetoxy-6-ethyl-3,7-dione regeuna program (114 mg, 59 %) As a light yellow syrup which solidified upon standing. _Rf : 0.49 (6: 4, heptane: EtOAc); ^{1 H NMR (700 MHz, CDCl} 3): δ = 4.09 (1H, dd, J 10.7, 3.4), 3.79 (1H, dd, J 10.8, 7.3), 2.76-2.73 (1H, m), 2.47 (1H, t, J 11.3), 2.28-2.17 (4H, m), 2.08 (1H, ddd, J 14.4, 5.3,2.7), 2.05 (3H, s), 2.05-2.03 (1H, m), 1.93-1.86 m), 1.83 (1H, dd, J 16.5,14.9), 1.75-1.50 (6H, m), 1.37-1.32 1.10-1.04 (1H, m), 1.03-1.02 (3H, d, J 6.7), 1.00-0.95 (1H, m), 0.81 (3H, t, J 7.4), 0.72 (3H, s); ^{13 C NMR (176 MHz, CDCl} 3): δ = 212.0 (C = O), 210.5 (C = O), 171.4 (OC = O), 69.4, 52.4, 52.2, 51.8, 50.0, 48.7, 43.8, 42.8, 38.7, 38.3, 36.7, 35.9, 35.6, 35.5, 27.8, 24.7, 22.9, 22.3, 21.0, 18.6, 17.3, 12.1, 11.8.

Example  13 - ( 5β , 6α , 20 S ) -6-ethyl-20- Hydroxymethyl - Pregnana -3,7- Dion Synthesis of

(5β, 6α, 20 S) -20- acetoxy-6-ethyl-3,7-dione regeuna program (96 mg, 0.23 mmol) in methanol (5 mL) the pH was dissolved solid sodium methoxide in 11 Lt; / RTI &gt; The mixture was stirred at 18 [deg.] C for 22 h and then neutralized (pH 7-8) with 4: 1 ethanol: acetic acid. The mixture was concentrated and partitioned between EtOAc (20 mL) and water (20 mL). The organic phase was washed with sodium chloride (20 mL of a 5% aqueous solution) and concentrated in vacuo. Purification of the residue by flash chromatography over silica gel (5β, 6α, 20 S) -6- ethyl -20-hydroxymethyl-3,7-dione regeuna program (67 mg, 78%) as a colorless syrup Lt; / RTI &gt;

^{1 H NMR (700 MHz, CDCl} 3): δ = 3.64 (1H, dd, J = 10.4, 2.9), 3.37 (1H, dd, J = 10.3, 7.1), 2.69 (1H, m), 2.47 (1H, t, J = 11.3), 2.30-2.16 (5H, m), 2.10-2.03 (2H, m), 1.94-1.80 (3H, m), 1.72-1.49 (6H, m), 1.43 (1H, br.s ), 1.33 (3H, s) , 1.32-1.17 (3H, m), 1.06 (3H, d, J = 6.7), 0.98 (1H, m), 0.81 (3H, t, J = 7.4), 0.71 (3H , s); ^{13 C NMR (176 MHz, CDCl} 3): δ = 212.1, 210.6, 67.8, 52.4, 52.2, 51.5, 50.0, 48.7, 43.7, 42.7, 38.8, 38.6, 38.3, 36.7, 35.9, 35.5, 27.9, 24.7, 22.9 , 22.3, 18.6, 16.8, 12.2, 11.8.

Example  14 - ( 3α , 5β , 6α , 20S) -6-ethyl-3- Hydroxy -7-oxo-23,24- D Nor-cholan-22-ol [or ( 3α , 5β , 6α , 20S) -6-ethyl-3- Hydroxy -20- Hydroxymethyl -Pregna-7-one &lt; / RTI &gt;

IPA (6.5 vol, 9 mL) of NaBH ₄ was a (136 mg, 3.6 mmol) cooled to-15 ℃, EtOAc (6.5 vol, 9 mL) of (5β, 6α, 20 S) -6- ethyl-3, A solution of 7-dioxo-23,24-dinor-cholan-22-ol (1.35 g, 0.3.6 mmol) was added dropwise over 10 min. After 20 min, the reaction mixture was warmed to ambient temperature and quenched by dropwise addition of 0.7 M aqueous H ₂ SO ₄ (7 vol, 9.45 mL) over 10 min. The reaction mixture was diluted with EtOAc (50 mL) and the organic phase was washed with H ₂ O (3 × 50 mL) and 5% aqueous NaCl (50 mL). The organic phase was dried over Na ₂ SO _4, filtered, and concentrated in vacuo at 40 ℃. Purification by column chromatography and concentration in vacuo at 40 ° C afforded (3?, 5?, 6?, 20S) -6-ethyl-3-hydroxy-7-oxo-23,24-dinor- As a white crystalline solid (0.83 g, 61%). ^{1 H NMR (700 MHz, CDCl} 3): δ = 3.64 (1H, dd, J = 10.5, 3.2), 3.53 (1H, m), 3.35 (1H, dd, J = 10.4, 7.1), 2.69 (1H, m), 2.35 (1H, t , J = 11.2), 2.20 (1H, m), 2.00 (1H, m), 1.92-1.67 (8H, m), 1.57-1.43 (3H, m), 1.34-1.23 ( 2H, m), 1.23 (3H , s), 1.21-1.10 (4H, m), 1.04 (3H, d, J = 6.6), 0.98-0.83 (2H, m), 0.80 (3H, t, J = 7.4 ), 0.67 (3H, s); ^{13 C NMR (176 MHz, CDCl} 3): δ = 212.9, 71.2, 67.9, 52.0, 51.6, 50.7, 50.0, 48.8, 43.7, 42.8, 38.9, 38.7, 35.7, 34.3, 31.8, 29.6, 27.9, 24.8, 23.5 , 21.9, 18.8, 16.8, 12.1, 12.0.

Example  15 - ( 3α , 5β , 6α , 7α , 20 S ) -6-ethyl-3,7- Dihydroxy -23, 24- D Nor-cholan-22-ol (or ( 3α , 5β , 6α , 7α , 20 S ) -6-ethyl-3,7- Dihydroxy -20- Hydroxymethyl - &lt; / RTI &gt;

THF (30 mL) and water (7.5 mL) of (3α, 5β, 6α, 20 S) -6- ethyl-3-hydroxy-7-oxo--23,24- Dino le-kolran 22-ol (0.83 cooling g, 2.2 mmol) to 0 ℃ and over the _{NaBH 4 (830 mg, 22 mmol} ) for 15 min was added in four divided minutes. It was added dropwise over a 2 M aqueous H ₂ SO ₄ (11 mL) then quenched by addition of H ₂ O (15 mL) for 10 min: 2 h after reaction mixture was warmed to room temperature and 1: 1 MeOH. The reaction mixture was diluted with EtOAc (100 mL) and washed with H ₂ O (100 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic phases washed with 5% aqueous NaCl (3 x 100 mL). The organic phase was dried over Na ₂ SO ₄ and was filtered and concentrated in vacuo at 40 ℃ (3α, 5β, 6α , 7α, 20 S) -6- ethyl-3,7-dihydroxy--23,24- Dino Le -Cholan-22-ol as a white solid (0.53 g, 64%). ^{1 H NMR (700 MHz, MeOD} ): δ = 3.64 (1H, s), 3.57 (1H, dd, J = 10.6, 3.1), 3.30 (1H, m), 3.23 (1H, dd, J = 10.5, 7.4 ), 2.00 (1H, m), 1.90-1.70 (6H, m), 1.59 (1H, m), 1.57-1.44 (6H, m), 1.42-1.27 1.13 (1H, m), 1.04 (3H, d, J = 6.6), 1.00 (1H, m), 0.91 (3H, s), 0.90 (3H, t, J = 7.7), 0,71 (3H, s ); ^{13 C NMR (176 MHz, MeOD} ): δ = 71.7, 69.7, 66.5, 52.5, 50.0, 45.5, 42.3, 41.7, 40.1, 39.5, 38.8, 35.3, 35.1, 33.1, 32.9, 29.8, 27.5, 23.2, 22.3, 22.0, 20.5, 15.9, 10.9, 10.6.

Example  16 - ( 3α , 5β , 6α , 7α ) -6-ethyl-3,7- Dihydroxy -23, 24- Dinor Synthesis of Cholan-22-Al

DMF (50 vol, 20 mL) of (3α, 5β, 6α, 7α , 20 S) -6- ethyl-3,7-dihydroxy--23,24- Dino le-kolran 22-ol (421 mg, 1.11 mmol) was cooled to 0 &lt; 0 &gt; C. (473 mg, 1.12 mmol) was added in portions. After 2.5 h, the reaction was quenched by addition of 10% aqueous NaHSO ₃ /2% aq. NaHCO ₃ (5 mL) (TLC, eluent 7: 3 EtOAc: heptane; visualized with cerium ammonium molybdate stain) Stir for 10 min. The mixture was diluted with EtOAc (100 mL) and 5% NaCl (5 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic phases were washed with 2 M aqueous NaOH (50 mL) and 5% aqueous NaCl (4 x 50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo at 40 ° C. (3α, 5β, 6α, 7α) -6-ethyl-3,7-dihydroxy-23,24-dinorcholan-22- (White foam, 230 mg) of ethyl-7-hydroxy-7-oxo-23,24-dinor-cholan-22-al. ^{1 H NMR (700 MHz, CDCl} 3): δ = 9.56 (1H, d, J = 3.4), 3.71 (1H, br s.), 3.44 - 3.36 (1H, m), 2.38 - 2.33 (1H, m) (2H, m), 1.94-1.86 (2H, m), 1.83-1.81 (2H, m), 1.80-1.78 (2H, m), 1.74-1.36 d, J = 6.8), 0.91 (3H, s), 0.88 (3H, t, J = 7.07), 0.71 (3H, s). ^{13 C NMR (176 MHz, CDCl} 3): δ = 205.1, 72.3, 70.9, 51.0, 49.9, 49.5, 45.1, 43.3, 41.2, 40.0, 39.3, 35.6, 35.5, 34.0, 33.4, 30.6, 27.1, 24.1, 23.1 , 22.2, 20.7, 13.5, 12.2, 11.6.

Example  17 - ( 3α , 5β , 6α , 7α ) -6-ethyl-3,7- Dihydroxy -22- Collen -24-oxo-ethyl ester

The HWE reagent was prepared by dropwise addition of TEPA (262 L, 1.32 mmol) to NaOEt (91 mg, 1.3 mmol) in CH ₂ Cl ₂ (2 mL) at 0 ° C. From 0 ℃ of the reaction mixture _{CH 2 Cl 2 (4 mL)} (3α, 5β, 6α, 7α) over 10 minutes, 6-ethyl-3,7-dihydroxy--23,24- Dino le-kolran - Was added dropwise to a solution of 22-Al (199 mg, 0.528 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour (TLC, eluent 1: 1 EtOAc: heptane; visualized by cerium ammonium molybdate staining). The mixture was diluted with H ₂ O (20 mL) and CH ₂ Cl ₂ (15 mL). The aqueous layer was separated and extracted with CH ₂ Cl ₂ (3 x 20 mL). The combined organic phases were dried over Na ₂ SO _4, filtered and concentrated. The crude product was purified by column chromatography to give (3?, 5?, 6?, 7?) -6-ethyl-3,7-dihydroxy-22-cholene-24-oic acid ethyl ester as a white foam (158 mg). The isolated product is purified by chromatography on silica gel using the desired (3?, 5?, 6?, 7?) - 6-ethyl-3,7-dihydroxy- Dihydroxy-3-oxo-22-cholene-24-oic acid ethyl ester. ^{1 H NMR (700 MHz, CDCl} 3): δ = 6.83 (1H, dd, J = 9.0, 15.6), 5.73 (1H, d, J = 15.3), 4.17 (2H, q, J = 7.1), 3.69 ( (2H, m), 1.76-1.62 (5H, m), 1.59 (1H, m), 3.40 (1H, m), 2.30-2.25 m), 1.54-1.34 (7H, m), 1.29 (3H, t, J = 7.1), 1.33-1.23 (6H, m), 1.09 0.90 (3H, t, J = 7.4), 0.68 (3H, s). ^{13 C NMR (176 MHz, CDCl} 3): δ = 167.1, 154.7, 119.0, 72.3, 70.8, 60.1, 54.9, 50.4, 45.2, 43.0, 41.0, 40.1, 39.8, 39.5, 35.6, 35.5, 34.0, 33.3, 30.6 , 28.2, 23.7, 23.1, 22.2, 20.7, 19.3, 14.3, 12.1, 11.7.

Example  18 - ( 3α , 5β , 6α , 7α ) -6-ethyl-3,7- Dihydroxy -Cholan-24-oic acid ethyl ester

10% palladium on carbon (79 mg) under argon was charged to the flask. A solution of (3?, 5?, 6?, 7?) - 6-ethyl-3,7-dihydroxy-22-cholen-24-oic acid ethyl ester (135 mg, 0.312 mmol) in EtOAc (51 vol, And purged with H ₂ . After 70 h (TLC, eluent 1: 1 EtOAc: heptane; visualized with anisaldehyde stain), the reaction mixture was filtered through a 0.45 um PTFE filter and the filter was washed with EtOAc (10 mL). (3.alpha., 5.beta., 6.alpha., 7.alpha.) - 6-ethyl-3,7-dihydroxycholan-24-oic acid ethyl ester (134 mg) -Ethyl-7-hydroxy-3-oxo-cholan-24-oic acid ethyl ester as a 4: 1 mixture. ^{1 H NMR (500 MHz, CDCl} 3): δ = 4.13 (2H, q, J = 7.2), 3.46 - 3.37 (1H, m), 2.41 - 2.32 (1H, m), 2.28 - 2.19 (1H, m) , 1.89-1.76 (6H, m), 1.76-1.57 (5H, m), 1.54-1.34 (12H, m), 1.27 (3H, t, J = 7.1), 1.25-1.24 0.88 (9H, m), 0.68 (3H, s). ^{13 C NMR (126 MHz, CDCl} 3): δ = 167.1, 154.7, 119.0, 72.3, 70.8, 60.1, 54.9, 50.4, 45.2, 43.0, 41.0, 40.1, 39.8, 39.5, 35.6, 35.5, 34.0, 33.3, 30.6 , 28.2, 23.7, 23.1, 22.2, 20.7, 19.3, 14.3, 12.1, 11.7.

Example  19 - ( 3α , 5β , 6α , 7α ) -6-ethyl-3,7- Dihydroxy Synthesis of cholan-24-oic acid (Obeticol)

To a solution of (3?, 5?, 6?, 7?) - 6-ethyl-3,7-dihydroxy-cholan-24-oic acid ethyl ester (118 mg, 0.272 mmol) in EtOH (34 vol, M aqueous NaOH (1.2 mL, 0.61 mmol) was added dropwise. The reaction mixture was stirred at 50 C for 2.5 h (TLC, eluent 1: 1 EtOAc: heptane; visualized with cerium ammonium molybdate stain) and 0.5 M aqueous NaOH (1 mL, 0.5 mmol) was added. After 1 h, the reaction was quenched with 3 M aqueous HCl (2 mL). The aqueous phase was separated and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over Na ₂ SO _4, filtered and concentrated in vacuo at 40 ℃. (108 mg, white foam) was added to a solution of (5β, 6α, 7α) - 6-ethyl-3,7-dihydroxy- Ethyl-3,7-dihydroxy-cholan-24-oic acid as a 4: 1 mixture. NMR data were consistent with reference samples of OCA.

Example  20 and Example  21 - ( 3α , 5β , 6α , 7β ) -6-ethyl-3,7- Dihydroxy -Cholan-24-oic acid (analog of obetic acid (OCA))

Example  20 - ( 5β , 6α , 7β ) -6-ethyl-7- Hydroxy Synthesis of 3-oxo-cholan-24-oic acid

To a solution of (6α, 7β) -6-ethyl-7-hydroxy-3-oxo-cholanoic acid ethyl ester (510 mg, 1.14 mmol) in IPA (20 mL) was added 0.5 M aqueous NaOH (10 mL) The mixture was heated at 60 &lt; 0 &gt; C for 2.5 h. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc (10 mL) and 10% aqueous citric acid (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with 10% aqueous NaCl (40 mL), dried over sodium sulfate and concentrated under reduced pressure. The material was used directly in the next step without purification.

Example  21 - ( 3α , 5β , 6α , 7β ) -6-ethyl-3,7- Dihydroxy -Cholan-24-oic acid (7-beta-hydroxy isoform of obetic acid (OCA))

To a solution of (6.alpha., 5.beta., 7.beta.) - 6-ethyl-7-hydroxy-3-oxo-cholan-24-oic acid ethyl ester (473 mg, 1.13 mmol) in EtOAc (20 mL) And the mixture was cooled in an ice bath. It was added _{NaBH 4 (214 mg, 5.65 mmol} ), and and so that the reaction mixture was warmed to room temperature and stirred for 17 h. EtOAc (10 mL) and 10% aqueous citric acid (15 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic phases were washed with 10% aqueous NaCl (15 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10-50% acetone in toluene) to give the desired product (300 mg, 63%) as a colorless solid. &Lt; ¹ &gt; H NMR (400 MHz, MeOD); δ = 3.45 (1H, m) , 3.08 (1H, dd, J 10.4, 9.4), 2.33 (1H, ddd, J 15.3, 9.8, 5.3), 2.20 (1H (ddd, J 16.2, 9.4, 6.9), 2.04 (1H, br. dt, J 12.2, 2.9), 1.98-1.76 (5H, m), 1.75-1.34 (10H, m), 1.33-1.00 (11H, m), 0.97 (3H, d, J 6.6, C21 _{-C H 3), 0.95 (3H} , s, C19-C H 3), 0.86 (3H, t, J 7.4, _{ethyl-C H 3), 0.72 (3H} , s, C18-C H 3); 13 C NMR (100 MHz, MeOD)? = 178.2, 76.3, 72.4, 57.8, 56.6, 45.2, 45.0, 44.7, 44.6, 41.7, 41.1, 36.7, 36.5, 35.6, 32.4, 32.0, 31.2, 30.8, 29.6, 27.9, 24.0, 22.6, 22.0, 18.9, 12.7, 11.5.

Example  22- Example  40 - Synthesis of additional epoxidation precursors

Example  22 - (20 S ) -20- Hydroxymethyl - Pregnana -4-en-3-one

(20 S) -20--hydroxymethyl-4-en-3-on-profile regeuna (HMPO) is Dino Le kolren aldehyde in the primary alcohol ((20S) -20- formyl-frame geuneu 4-ene- 3-one) and NaBH ₄ (Barry M. Trost, Alvin C. Lavoie J. Am. Chem . Soc . , 1983 , 105 (15), 5075-5090) .

Example  23 - (20 S ) -20- Acetoxymethyl - Pregnana -4,6- Dien 3-one

HMPO (300 g, 0.913 mol) was added to the reaction vessel and AcOH (0.9 L) and toluene (0.3 L) were added with stirring. Subsequently, p -chloranyl (245 g, 1.00 mol) was added and the reaction mixture was heated to 110 &lt; 0 &gt; C and held at this temperature for 6 h. The mixture was then cooled to 5 &lt; 0 &gt; C and held at that temperature for 2 h. The resulting solid was filtered, the filter-cake was washed with cold pre-mixed 3: 1 AcOH: toluene (4 x 150 mL) and the filtrate was concentrated in vacuo. The residue was dissolved in acetone (900 mL) and then 3.5% w / w aqueous NaOH (3.0 L) was added dropwise while maintaining the temperature below 30 &lt; 0 &gt; C. The resulting solid was collected by filtration and the filter cake was washed with pre-mixed 1: 1 acetone: water (1.5 L). The filter cake was then slurried in 1: 1 acetone: water (600 mL) at 20 &lt; 0 &gt; C, filtered and washed with pre-mixed 1: 1 acetone: water (1.0 L). The solid was dried under vacuum at 65-70 [deg.] C to give the desired product (224 g, 67%) as a tan solid. _{δH (400 MHz, CDCl 3)} ; 6.17-6.12 (1H, m, C6- C H), 6.10 (1H, dd, J 9.9, 2.0, C7-C H), 5.68 (1H, s, C4-C H), 4.10 (1H, dd, J 10.7, 3.5, C22-C H a H b), 3.79 (1H, dd, J 10.7, 7.4, C22-CH a H b), 2.58 (1H, ddd, J 17.9, 14.4, 5.4, C2-C H a _{H b), 2.49-2.39 (1H,} m, C2-CH a H b), 2.20 (1H, brt, J 10.2, C8-C H), 2.10-1.97 (1H, m), 2.06 (3H, s, _{OC (O) C H 3)} , 1.96-1.66 (4H, m), 1.62-1.53 (1H, m), 1.52-1.16 (8H, m), 1.12 (3H, s, C19-C H 3), 1.04 (3H, d, J 6.6, C21-C H 3), 0.79 (3H, s, C18-C H 3); _{δC (100 MHz, CDCl 3)} ; 199.6, 171.3, 163.8, 141.2, 127.9, 123.6, 69.4, 53.2, 52.6, 50.7, 43.6, 39.4, 37.7, 36.1, 35.8, 33.9, 33.9, 27.6, 23.8, 21.0, 20.7, 17.1, 16.3, 11.9.

Example  24 - (20 S ) -20- Hydroxymethyl - Pregnana -4,6- Dien 3-one

(20 S ) -20-acetoxymethyl-pregna-4,6-dien-3-one (25 g, 67.5 mmol) was suspended in MeOH (250 mL) and sodium methoxide 25% w / v solution in MeOH). The resulting mixture was stirred at room temperature for 4 h. The pH was adjusted to pH 4 by addition of Finex CS08GH ⁺ resin. The mixture was filtered and the filtrate was concentrated under reduced pressure while co-evaporating with PhMe (2 x 250 mL). The residue was dried in a vacuum oven at 30 &lt; 0 &gt; C for 48 h to give the desired product (22.15 g, 99%) as a light brown solid. _{δH (400 MHz, CDCl 3)} ; 6.16-6.11 (1H, m, C7- C H), 6.09 (1H, dd, J 9.9, 2.3, C6-C H), 5.67 (1H, s, C4-C H), 3.65 (1H, dd, J 10.5, 3.3, C22-C H a H b), 3.59 (1H, dd, J 10.5, 6.7, C22-CH a H b), 2.57 (1H, ddd, J 18.0, 14.4, 5.5, C2- C H a _{H b), 2.45-2.38 (1H,} m, C2-CH a H b), 2.19 (1H, brt, J 10.4, C8-C H), 2.11-1.76 (5H, m), 1.71 (1H, td, J 13.9, 5.3, C1-C H a H b), 1.65-1.16 (9H, m), 1.11 (3H, s, C19-C H 3), 1.06 (3H, d, J 6.6, C21-C H 3 ), 0.78 (3H, s, C18-C H 3); _{δC (100 MHz, CDCl 3)} ; 199.7, 164.0, 141.4, 127.9, 123.5, 67.8, 53.2, 52.3, 50.7, 43.5, 39.4, 38.7, 37.8, 36.1, 33.9, 33.9, 27.6, 23.8, 20.7, 16.7, 16.3, 12.0.

Example  25 - (20 S ) -20- tert-Butyldimethylsilyloxymethyl - Pregnana -4,6- Dien 3-one

(20 S ) -20-hydroxymethyl-pregna-4,6-dien-3-one (1.00 g, 3.04 mmol) was dissolved in anhydrous CH ₂ Cl ₂ (10 mL) and the solution was cooled to 0 ° C . Imidazole (414 mg, 6.09 mmol) and TBDMSCl (551 mg, 3.65 mmol) were added and the reaction mixture was stirred at 0 <0> C for 4 h. The reaction mixture was allowed to warm to room temperature and CH ₂ Cl ₂ (10 mL) and water (20 mL) were added. The layers were separated and the organic phase was washed with water (20 mL), saturated aqueous sodium chloride (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-25% EtOAc in heptane) to give the desired product (890 mg, 66%) as a light yellow solid. _{δH (400 MHz, CDCl 3)} ; 6.14 (1H, dd, J 9.9 , 1.3, C7-C H), 6.09 (1H, dd, J 9.8, 2.4, C6-C H), 5.66 (1H, s, C4-C H), 3.58 (1H, dd, J 9.7, 3.4, C22 -C H a H b), 3.28 (1H, dd, J 9.7, 7.2, C22-CH a H b), 2.57 (1H, ddd, J 17.9, 14.4, 5.4, C2- _{C H a H b), 2.47-2.37} (1H, m, C2-CH a H b), 2.19 (1H, brt, J 10.3, C8-C H), 2.07 (1H, dt, J 12.9, 3.3), 2.00 (1H, dd, J 8.5 , 2.1), 1.94-1.63 (3H, m), 1.60-1.15 (9H, m), 1.11 (3H, s, C19-C H 3), 1.00 (3H, d, J _{6.7, C21-C H 3)} , 0.89 (9H, s, SiC (C H 3) 3), 0.77 (3H, s, C18-C H 3), 0.03 (6H, s, Si (C H 3) 2 ); _{δC (100 MHz, CDCl 3)} ; 16.9, 16.3.9, 141.5, 127.8, 123.5, 67.7, 53.2, 52.5, 50.7, 43.5, 39.4, 39.0, 37.8, 36.1, 34.0, 33.9, 27.6, 25.9, 25.9, 25.9, 23.9, 20.7, 18.4, 16.9, 16.3, 12.0, -5.3, -5.4; (IR) v _max (cm ^-1 ): 3027, 2956, 2930, 2891, 2857, 1677, 1077, 753; HRMS (ESI-TOF) m / z: C 28 H 46 O calculated for ^{_{2 Si (M + H) +}} 442.3267, measured 443.3338.

Example  26 - (20 S ) - tert - Butyl diphenylsilyloxymethyl - Pregnana -4,6- Dien 3-one

Under argon DMF (5mL, 10 vol) of (20 S) - hydroxymethyl - TBDPSCl To a solution of 4,6-dien-3-one regeuna program (500 mg, 1.5 mmol) ( 510 mg, 1.2 eq) and Imidazole (217 mg, 2 eq) was added and the reaction mixture was stirred at 20 &lt; 0 &gt; C. After 16 h, the reaction mixture was poured into H ₂ O (50 mL) and extracted with TBME (2 x 20 mL). The combined organic phases were washed with aqueous 5% w / v NaCl (2 x 20 mL) , dried over Na ₂ SO _4, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel (20 S) - to give a profile regeuna 4,6-diene-3-one (742 mg, 86%) - tert - butyl-diphenyl-silyloxy methyl. R _f 0.69 (1: 1, EtOAc: heptane); ^{1 H NMR (700 MHz, CDCl} 3): 7.67 -7.65 (4H, m), 7.43 - 7.40 (2H, m), 7.39-7.36 (4H, m), 6.13-6.07 (2H, m), 5.66 (1H (1H, m), 3.61 (1H, dd, J 9.3, 3.3), 3.37 (1H, dd, J 9.8, 6.9), 2.57 (1H, ddd, J 18.0,14.6,5.5) , 2.17 (1H, t, J 8.3), 2.06 (1H, dt, J 12.9, 3.4), 2.00 (1H, ddd, J 13.2, 5.4, 2.0), 1.75-1.67 (3H, m), 1.58-1.53 (1H, m), 1.43 (1H, qd, J 12.9, 3.9), 1.32-1.16 (7H, m), 1.11 0.73 (3 H, s); ^{13 C NMR (175 MHz, CDCl} 3): 199.7, 164.0, 141.5, 135.7, 135.6, 134.1, 129.5, 127.8, 127.6, 127.5, 123.5, 68.5, 53.2, 50.6, 43.5, 39.4, 39.0, 37.8, 36.1, 34.0 , 33.9, 27.5, 26.9, 23.8, 20.7, 19.4, 17.2, 16.3, 14.1, 11.9.

Example  27- (20S) -20- Formyl - Pregnana -4,6- Dien 3-one

(20 S ) -20-hydroxymethyl-pregna-4,6-dien-3-one (3.01 g, 9.16 mmol) was dissolved in anhydrous CH ₂ Cl ₂ (60 ml) and the solution was cooled to 0 ° C . Dess-Martin periodinane (5.83 g, 13.7 mmol) was added in portions over 10 minutes and the reaction mixture allowed to warm slowly to room temperature and stirred for 22 h. It was added to split minutes 1 mixture (75 ml): The mixture was cooled to 0 ℃ and 10% of the first aqueous Na ₂ S ₂ O ₃ and 2% aqueous NaHCO _3. CH ₂ Cl ₂ (50 mL) was added and the layers were separated. The aqueous phase was extracted with CH ₂ Cl ₂ (2 × 50 mL) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-25% EtOAc in heptane) to give the desired product (1.23 g, 41%) as a light yellow solid. _{δH (400 MHz, CDCl 3)} ; 9.59 (1H, d, J 3.2 , C H O), 6.12 (2H, s, C6-C H and C7-C H), 5.68 ( 1H, s, C4-C H), 2.58 (1H, ddd, J 17.9, 14.4, 5.4), 2.49-2.36 (2H, m), 2.22 (1H, t, J 10.6, C8-C H), 2.08-1.81 (4H, m), 1.73 (1H, td, J 13.8, 5.1 _{, C1-C H a H b} ), 1.65-1.20 (8H, m), 1.15 (3H, d, J 6.9, C21-C H 3), 1.13 (3H, s, C19-C H 3), 0.82 ( 3H, d, C18-C H 3); _{δC (100 MHz, CDCl 3)} ; 204.6, 199.5, 163.6, 140.8, 128.1, 123.7, 52.8, 50.8, 50.7, 49.4, 44.0, 39.2, 37.6, 36.0, 33.9, 33.9, 27.0, 24.1, 20.6, 16.3, 13.5, 12.3; (IR) v _max (cm ^-1 ): 3030, 2934, 2706, 1717, 1655, 1615, 15811; HRMS (ESI-TOF) m / z: C 22 H 30 O 2 with (M + H) ⁺ calculated for 326.2246; Measurement 327.2318.

Example  28- (20S) -20- ( Ethylene dioxymethyl ) - Pregnana -4,6- Dien 3-one

Under an argon atmosphere, _{CH 2 Cl 2 (5 vol,} 20 mL) of (20 S) -20- formyl-4,6-diene To a solution of the program regeuna 3-one (3.89 g, 12 mmol) 1,2 -Bis (trimethylsilyloxy) ethane (2.94 mL, 12 mmol). The reaction mixture was cooled to -78 ° C and TMSOTf (108 μL, 0.6 mmol) was added. After 2 h, the reaction mixture was diluted with CH ₂ Cl ₂ (100 mL) and washed with water (2 × 100 mL) and 5% aqueous NaCl (100 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Purification by column chromatography on silica gel gave the desired product (2.42 g, 55%) as a colorless crystalline solid. _{δH (700 MHz, CDCl 3)} ; 6.12 (2H, m), 5.67 (1H, m), 4.86 (1H, d, J 2.0), 3.94 (2H, m), 3.86 (2H, m,), 2.56 (1H, m), 2.43 (1H, m), 2.19 (1H, t , J 10.6), 2.05-1.95 (3H, m), 1.85 to 1.20 (12H, m), 1.11 (3H, s), 0.95 (3H, d, J 6.7), 0.77 ( 3H, s). _{δC (176 MHz, CDCl 3)} ; 199.7, 163.9, 141.4, 127.9, 123.6, 105.6, 65.3, 65.1, 52.9, 52.2, 50.6, 43.7, 39.3, 39.3, 37.8, 36.1, 34.0, 33.9, 27.3, 23.9, 20.67, 16.3, 11.7, 11.6.

Example  29 - (20 S ) -20- (1-mesyl Oxymethyl ) - Pregnana -4,6- Dien 3-one

Pyridine (10 mL) of (20 S) -20- hydroxy-methyl-DMAP (19 mg, 0.15 mmol) to a solution of 4,6-dien-3-one profile regeuna (1.00 g, 3.05 mmol) was added . MsCl (1.18 mL, 15.2 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was cooled in an ice bath and water (10 mL) was added dropwise. EtOAc (20 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with 2 M aqueous HCl (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc in heptane) to give the desired product (1.01 g, 82%) as an orange solid. _{δH (400 MHz, CDCl 3)} ; 6.12 (2H, brs, C6- C H and C7-C H), 5.68 ( 1H, s, C4-C H), 4.21 (1H, dd, J 9.4, 3.2, C22-C H a H b), 4.01 (1H, dd, J 9.4, 6.6, C22-CH a H b), 3.01 (3H, s, OS (O 2) C H 3), 2.58 (1H, ddd, J 18.0, 14.4, 5.5, C2-C _{H a H b), 2.49-2.39 (} 1H, m, C2-CH a H b), 2.21 (1H, brt, J 10.5, C8-C H), 2.09-1.80 (5H, m), 1.73 (1H, td, J 13.8, 5.2, C1 -C H a H b), 1.63-1.53 (1H, m), 1.52-1.18 (7H, m), 1.13 (3H, s, C19-C H 3), 1.12 (3H , d, J 6.1, C 21 -C ₃ H ₃ ), 0.80 (3H, s, C 18 -C H ₃ ); _{δC (100 MHz, CDCl 3)} ; 199.5, 163.6, 140.9, 128.0, 123.7, 74.8, 53.1, 51.8, 50.6, 43.6, 39.3, 37.7, 37.2, 36.3, 36.0, 33.9, 33.9, 27.5, 23.8, 20.6, 16.9, 16.3, 12.0.

Example  30 - (20 S ) -20- ( Bromomethyl ) - Pregnana -4,6- Dien 3-one

In anhydrous _{CH 2 Cl 2 (10 mL)} (20 S) -20- hydroxymethyl-four to a solution of 4,6-dien-3-one profile regeuna (1.00 g, 3.05 mmol) carbon tetrabromide (1.52 g, 4.57 mmol). Triphenylphosphine (1.20 g, 4.57 mmol) was added and the mixture was heated at reflux for 2 h. The reaction mixture was allowed to cool to room temperature and water (20 mL) was added. The layers were separated and the organic layer was washed with 5% aqueous NaHCO ₃ (20 mL), 10% aqueous NaCl (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-25% acetone in heptane) to give the desired product (980 mg, 82%) as a light yellow crystalline solid. _{δH (400 MHz, CDCl 3)} ; 6.09-6.00 (2H, m, C6 H and C7 H), 5.59 (1H, s, C4 H), 3.43 (1H, dd, J 9.8, 2.7, C22 H a H b), 3.29 (1H, dd, J _{9.8, 5.8, C22H a H b} ), 2.50 (1H, ddd, J 17.9, 14.4, 5.4, C2 H a H b), 2.40-2.30 (1H, m, C2H a H b), 2.13 (1H, brt, J 9.8, C8 H), 2.01-1.57 (5H, m), 1.55-1.45 (1H, m), 1.44-1.10 (8H, m), 1.05 (3H, s, C19 H 3), 1.03 (3H, d , J 6.5, C 21 H ₃ ), 0.72 (3H, s, C 18 H ₃ ); _{δC (100 MHz, CDCl 3)} ; 199.2, 163.6, 141.0, 127.9, 123.6, 53.5, 53.1, 50.6, 43.4, 43.3, 39.2, 37.7, 37.6, 36.0, 33.9, 33.9, 27.4, 23.6, 20.6, 18.6, 16.3, 12.3;

Example  31 - (20 S ) - ( N - Phthalimidomethyl ) - Pregnana -4,6- Dien 3-one

(20 S ) -bromomethyl-pregna-4,6-dien-3-one (1.25 g, 3.2 mmol) was dissolved in DMF (25 mL, 20 vol) and potassium phthalimide (0.65 g, 1.1 eq ). The mixture was stirred at 50 &lt; 0 &gt; C under argon for 65 h and cooled to 25 &lt; 0 &gt; C. TBME (80 mL, 64 vol) was added and the reaction mixture was washed with water (80 mL, 64 vol). Separating the aqueous phase and, TBME The combined extracts and organic phase (80 mL) 0.2 M NaOH ( 80 mL), washed, and concentrated to an aqueous 5% w / v NaCl (80 mL) (20 S) - (N - Phthalimido) -propane-4,6-dien-3-one (0.97 g, 66%). _Rf : 0.30 (3: 7, EtOAc: heptane); ^{1 H NMR (700 MHz, CDCl} 3): 7.84 (2H, m), 7.72 (2H, m), 6.15 (1H, dd, J 9.7, 1.4), 6.11 (1H, dd, J 9.8, 2.7), 5.67 (1H, s), 3.65 (1H, dd, J 13.3, 3.8), 3.44 (1H, dd, J 13.6, 10.5), 2.57 (1H, ddd, J 17.8, 14.4, 5.4), 2.43 , 2.21 (1H, t, J 10.6), 2.11-2.03 (2H, m), 2.02-1.96 (2H, m), 1.87 (1H, m), 1.72 (1H, td, J 13.9, 5.1) (1H, m), 1.55 (1H, m), 1.43 (1H, qd, J 13.1, 4.0), 1.36 , d, J6.6), 0.80, (3H, s); ^13.3 C NMR (175 MHz, CDCl ₃ ): 199.7, 168.8, 163.9, 141.3, 133.9, 132.1, 127.9, 123.6, 123.2, 54.5, 53.2, 50.6, 43.8, 43.7, 39.4, 37.7, 36.2, , 27.8, 23.9, 20.6, 17.0, 16.3, 12.0.

Example  32 - 23- Ethoxy formyl -3-oxo-4,6- Cola dien -24-oxo-ethyl ester

Sodium hydride (60% dispersion in mineral oil, 226 mg, 5.64 mmol) was suspended in anhydrous THF (10 mL) and the mixture was cooled to 0 <0> C. Diethyl malonate (1.17 mL, 7.68 mmol) was added dropwise and the mixture was stirred at 0 &lt; 0 &gt; C for 15 min. 18, the program regeuna-4,6-dien-3-one (1.00 g, 2.56 mmol) was added dropwise and the reaction mixture refluxed a solution of-anhydrous THF (10 mL) of (20 S) -20- (bromomethyl) h. The reaction mixture was allowed to cool to room temperature and water (10 mL) was added. EtOAc (25 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with 10% aqueous NaCl (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-25% acetone in heptane) to give the desired product (1.00 g, 83%) as a clear oil. _{δH (400 MHz, CDCl 3)} ; 6.17-6.07 (2H, m, C6 H and C7 H), 5.67 (1H, s, C4 H), 4.29-4.14 (4H, m, 2x C (O) OC H 2), 3.44 (1H, dd, J _{10.9, 3.7, EtO 2 CC H} ), 2.57 (1H, ddd, J 17.9, 14.4, 5.4, C2 H a H b), 2.43 (1H, dddd, J 17.8, 5.1, 2.0, 0.8, C2H a H b) , 2.24-2.12 (2H, m), 2.10-1.93 (3H, m), 1.87-1.77 (1H, m), 1.71 (1H, td, J 16.2, 5.2, C1 H a H b), 1.59-1.35 ( 4H, m), 1.34-1.14 (12H , m), 1.11 (3H, s, C18 H 3), 0.96 (3H, d, J 6.2, C21 H 3), 0.75 (3H, s, C19 H 3); _{δC (100 MHz, CDCl 3)} ; 37.9, 34.0, 34.9, 33.9, 28.0, 23.7, 20.7, 18.2, 37.0, 37.5, 39.5, 16.3, 14.2, 14.1, 11.9.

Example  33 - 23- Cyano -24- Nord -Cyclo-4,6-dien-3-one

(20 S ) -20- Bromomethyl -3,3- Ethylene dioxy -4- Preganen  And (20 S ) -20- Bromomethyl Synthesis of -3,3-ethylenedioxy-5-prenene

To a solution of toluene (30 mL) of (20 S) -20- bromomethyl-4 frame geunen 3-one (1.00 g, 2.59 mmol) and ethylene glycol (2.0 mL, 36.25 mmol) p TSA.H 2 O (9.86 mg, 0.05 mmol) was added and the mixture was heated to reflux using a Dean Stark apparatus for 5 h. The reaction mixture was allowed to cool to room temperature and then poured into 5% aqueous NaHCO ₃ (30 mL). The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was used in the next step without purification. The sample was purified by column chromatography to yield the (heptane / EtOAc) (20 S) -20- bromomethyl-3,3-ethylenedioxy-4 frame geunen and (20 S) -20- bromo-methyl-3 , A mixture of 3-ethylenedioxy-5-pregene was provided in 68% yield (the ratio of? ⁵ :? ⁴ was approximately 3.6: 1). _{δH (700 MHz, CDCl 3)} ; 5.35 (0.8H, dt, J = 4.4, 2.2), 5.23 (0.2H, s), 4.02-3.96 (4H, m, C H 2 O), 3.51 (0.8H, dd, J 9.7, 2.7), 3.51 Dd, J 9.7, 6.0), 3.33 (0.2H, dd, J 9.7, 6.1), 2.56 (0.8H, dq, J 14.1, 2.9), 2.20 0.2H, td, J 13.9, 4.9 , 1.8), 2.12 (0.8H, dd, J 14.2, 2.9), 2.05 (0.2H, ddd, J 14.0, 4.2, 2.4), 1.99-1.93 (2H, m), (2H, m), 1.74-1.62 (4H, m), 1.60 (0.8H, s), 1.561.51 (1H, m), 1.50-1.41 m), 1.37-1.25 (3H, m ), 1.21 (1H, td, J 6.5, 4.2), 1.17-1.04 (3H, m), 1.09 (3H, d, J 6.4), 1.03 (3H, s), 1.01-0.84 (0.8H, m), 0.71 (2.4H, s), 0.70 (0.6H, s); _{δC (176 MHz, CDCl 3)} ; 37.6, 43.5, 42.5, 42.4, 41.8, 39.5, 39.5, 37.9, 37.8, 37.4, 36.6, 36.3, 35.8, 34.9, 32.4, 32.1, 31.9, 31.9, 31.7, 31.1, 30.0, 27.6, 27.6, 24.2, 24.1, 21.0, 18.9, 18.7, 18.6, 17.6, 12.3, 12.2.

3,3- Ethylene dioxy -4- Colleno -24-nitrile and 3,3- Ethylene dioxy -5- Colleno -24-nitrile

Procedure A

A solution of MeCN (26.0 mg, 0.63 mmol) in THF (1.85 mL) was cooled to -78 C under argon and nBuLi (0.32 mL, 2 M in cyclohexane, 0.63 mmol) was added dropwise over 2 min. THF (2.15 mL) in the (20 S) -20- bromomethyl-3,3-ethylenedioxy-4 frame geunen and (20 S) -20- bromomethyl-3,3-ethylenedioxy -5 -Prensene (185 mg, 0.423 mmol) was added dropwise to this mixture over 30 min. The reaction mixture was allowed to warm to 0 ℃ over 4 h, then cooled to -78 ℃, quenched with 10% aqueous NH ₄ Cl (3 mL). The reaction mixture was diluted with EtOAc (20 mL) and 10% aqueous NH ₄ Cl (20 mL) and the organic phase was separated. The aqueous phase was extracted with EtOAc (20 mL) and the combined organic phases were washed with 5% aqueous NaCl (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using heptane: EtOAc (5: 1) as eluent. A fraction containing 3,3-ethylenedioxy-4-choleno-24-nitrile and 3,3-ethylenedioxy-5-choleno-24-nitrile was obtained in 49% yield (Δ ⁵ : Δ ⁴ Of about 7: 1). _{δH (700 MHz, CDCl 3)} ; (0.9H, dt, J 4.5, 2.2), 5.2 (0.1H, br s), 4.02-3.86 (4H, m), 2.56 (0.9H, dq, J 14.2, 2.9), 2.39-2.34 , m), 2.34 (0.9H, ddd, J 16.9, 8.6, 5.1), 2.27 (0.9H, dt, J 16.8, 8.4), 2.27 (0.1H, dt, J 16.8, 8.4), 2.20 (0.1H, td, J 13.9, 5.0, 1.8 ), 2.12 (0.9H, dd, J 14.2, 3.0), 2.05 (0.1H, ddd, J 13.8, 4.4, 2.2), 2.01-1.95 (2H, m), 1.87-1.75 (2H, m), 1.50-1.52 (2H, m), 1.39-1.25 (4.6H, m) , m), 1.18 (1H, td, J 6.5, 4.2), 1.14-0.99 (4H, m), 1.03 (3H, s), 0.96 (2.7H, d, J 6.6), 0.94 (0.3H, d, J 6.7), 0.88 (0.9H, t, J 14.3), 0.70 (2.7H, s), 0.70 (0.3H, s); _{δC (176 MHz, CDCl 3)} ; 39.6, 39.7, 37.4, 36.6, 36.3, 35.7, 42.6, 42.5, 41.8, 17.2, 34.9, 32.4, 32.1, 31.9, 31.9, 31.7, 31.6, 31.5, 31.1, 30.0, 29.7, 28.1, 28.1, 24.2, 24.1, 22.7, 21.0, 18.9, 17.9, 17.9, 17.6, 14.3, 14.2, 14.1, 12.0, 11.9.

Procedure B

A solution of MeCN (2.06 mL, 39.43 mmol) in THF (34 mL) was added over 1.2 h to a solution of n BuLi (19.72 mL, 2 M in cyclohexane, 39.43 mmol) in THF Lt; / RTI &gt; The resulting white suspension, the THF (69 mL) (20 S ) -20- bromomethyl-3,3-ethylenedioxy-4 frame geunen and (20 S) -20- bromomethyl 3,3 -Ethylenedioxy-5-prenene (6.9 g, 15.77 mmol) was added dropwise over 1.2 h. The thick suspension formed was allowed to warm to 0 &lt; 0 &gt; C over 15 min and water (69 mL) was added dropwise. The layers were separated and the aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with 5% aqueous NaCl (2 x 100 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of EtOAc in heptane as eluent. A fraction containing 3,3-ethylenedioxy-4-choleno-24-nitrile and 3,3-ethylenedioxy-5-choleno-24-nitrile was obtained, (Mass 3.88 g).

3-oxo-4- Colleno -24-nitrile

To a solution of 3,3-ethylenedioxy-4-choleno-24-nitrile and 3,3-ethylenedioxy-5-choleno-24-nitrile (3.75 g, 9.43 mmol) in EtOH (75 mL) Was added a solution of H ₂ SO ₄ (1 mL, conc, 18.86 mmol) in THF (7.5 mL). The reaction mixture was heated at reflux for 30 min and cooled to room temperature. The white solid was removed by filtration and the filter cake was washed with EtOH (2 x 20 mL). The wash and filtrate were combined, pyridine (3 mL) was added and the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 1 M aqueous H ₂ SO ₄ (100 mL), 5% aqueous NaHCO ₃ (100 mL), 5% aqueous NaCl (2 x 100 mL) &Lt; / RTI &gt; and concentrated under reduced pressure to give the desired product (2.36 g). ^{1 H NMR (700 MHz, CDCl} 3): δ = 5.72 (1H, s, C4-C H), 2.45-2.25 (6H, m), 2.04-2.00 (2H, m), 1.89-1.82 (3H, m ), 1.69 (1H, td, J 7.0, 4.6), 1.67-1.62 (1H, m), 1.59-1.51 (3H, m), 1.44 m), 0.73 (3H, m), 1.20-1.10 (3H, m), 1.18 , s); ^{13 C NMR (176 MHz, CDCl} 3): δ = 199.6 (C = O), 171.4 (C = CH), 123.8 (C = C H), 120.2 (CN), 55.8, 55.5, 53.7, 42.6, 39.6, 38.6, 35.7, 35.6, 35.1, 34.0, 32.9, 32.0, 31.5, 28.1, 24.1, 21.0, 17.9, 17.4, 14.3, 12.0.

3-oxo-4,6- Coladieno -24-nitrile

To a solution of 3-oxo-4-choleno-24-nitrile (2.25 g, 0.64 mmol) in toluene (2.25 mL) and AcOH (6.75 mL) was added chloranyl (1.72 g, 0.70 mmol). The mixture was heated at 100 &lt; 0 &gt; C for 45 min and allowed to cool to room temperature. The mixture was filtered while washing with AcOH: toluene (3: 1, 20 mL) and the filtrate was combined and concentrated under reduced pressure. The residue was concentrated from toluene (3 x 40 mL) and acetone (3 x 40 mL) and then dissolved in acetone (6.75 mL). The solution was poured into an aqueous solution of NaOH (22.5 mL, 3% w / v) and the resulting sticky solid was collected by filtration and washed with water: acetone (2 x 20 mL, 2: 1). The solids were purified by chromatography on silica gel using a gradient of EtOAc in heptane as eluent to give the desired product as a yellow solid (1.33 g, 59% yield). ^{1 H NMR (700 MHz, CDCl} 3): δ = 6.13 (1H, d, J 11.0), 6.10 (1H, dd, J 9.8, 2.3), 5.67 (1H, s), 2.57 (1H, ddd, J 17.9 , 14.5, 5.4), 2.45-2.41 (1H, m), 2.39 (1H, ddd, J 17.0, 8.3, 5.1), 2.29 (2H, m), 1.71 (1H, td), 2.05 (1H, dt, J 12.9,3.4), 2.00 (1H, ddd, J 13.2, 5.3, 2.0), 1.95-1.89 , J 9.7,1.3), 1.62-1.54 (2H, m), 1.44 (1H, qd, J 9.7,1.3), 1.41-1.34 (2H, m), 1.30 (1H, ddd, J 24.0, 11.7, 5.8) , 1.25-1.19 (3H, m), 1.17 (1H, q, J 9.5), 1.11 (3H, s), 0.97 (3H, d, J 6.7), 0.78 (3H, s); ^{13 C NMR (176 MHz, CDCl} 3): δ = 199.6, 163.8, 141.1, 127.9, 123.6, 120.1, 55.4, 53.4, 50.6, 43.6, 39.5, 37.7, 36.0, 35.2, 34.0, 33.9, 31.4, 28.1, 23.7 , 20.6, 17.9, 16.3, 14.4, 11.9.

Example  34 - (20 S ) -20- (1- Aminomethyl ) - Pregnana -4,6- Dien 3-one

(20 S ) - Tosyloxymethyl - Pregnana -4,6- Dien 3-one

To a solution of (20 S ) -hydroxymethyl-pregna-4,6-dien-3-one (1.50 g, 4.58 mmol) in pyridine (50 mL) at 0 ° C was added p -toluenesulfonyl chloride (1.79 g, 9.39 mmol). The reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 h, and at ambient temperature for 17 h. The reaction was quenched with 1 M aqueous HCl (75 mL) and diluted with ethyl acetate (150 mL). The organic phase was separated and washed with water (50 mL), 5% aqueous sodium bicarbonate (75 mL), 5% aqueous NaCl (50 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (heptane-EtOAc) to give the desired product (1.59 g, 72%) as a yellow powder. _Rf : 0.36 (3: 2, heptane: ethyl acetate); ^{1 H NMR (700 MHz, CDCl} 3): δ = 7.78 (2H, d, J 8.2, Ar-H), 7.35 (2H, d, J 8.2, Ar-H), 6.10 (2H, br s, C6H. and C7H), 5.67 (1H, s , C4H), 3.97 (1H, dd, J 9.3, 3.2, C22H), 3.80 (1H, dd, J 9.3, 6.4, C22H), 2.56 (1H, ddd, J 17.6, 14.6, 5.6, C2H), 2.45-2.41 (4H, m, C2H and _{Ts-C H 3), 2.17} (1H, t, J 10.5), 2.01-1.96 (2H, m), 1.80-1.67 (4H, m ), 1.54 (1H, d, J 13.5, 3.1), 1.41 (1H, qd, J 13.1, 3.9), 1.30-1.23 (3H, m), 1.23-1.17 C19H), 1.00 (3H, d, J 6.7, C21H), 0.73 (3H, s, C18H). ¹³ C NMR (176 MHz, CDCl ₃ ):? = 197.9, 162.0, 142.9, 139.2, 131.3, 128.0, 126.2, 126.1, 121.9, 73.6, 51.3, 49.9, 48.8, 41.7, 37.4, 35.9, 34.4, , 32.1, 25.6, 21.9, 20.0, 18.8, 15.1, 14.5, 10.1.

(20 S ) - Azidomethyl - Pregnana -4,6- Dien 3-one

DMF (24 mL) and water (59 ㎕) of (20 S) - tosyloxy-methyl-phe regeuna O To a suspension of sodium 4,6-dien-3-one (1.58 g, 3.27 mmol) hydrazide (273 mg, 4.20 mmol). The reaction mixture was heated to 70 &lt; 0 &gt; C and stirred for 1 h. The reaction was quenched with 2% aqueous sodium bicarbonate solution (50 mL) at 40 &lt; 0 &gt; C and diluted with ethyl acetate (100 mL). The layers were separated and the organic layer was washed with 2% aqueous sodium bicarbonate (50 mL), 5% aqueous NaCl (50 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (heptane-EtOAc) to give the desired product (1.01 g, 91% yield) as a colorless crystalline solid. _Rf : 0.54 (3: 2, heptane: ethyl acetate); ^{1 H NMR (700 MHz, CDCl} 3): δ = 6.12 (1H, d, J 9.9, C6H), 6.10 (1H, dd, J 9.9, 2.1, C7H), 5.67 (1H, s, C4H), 3.38 ( M, 1H, dd, J 11.9,3.3, C22H), 3.07 (1H, dd, J 11.9, 7.3, C22H), 2.57 (1H, ddd, J 17.8, 14.7, 5.4, C2H), 2.46-2.41 C2H), 2.17 (1H, t , J 10.6), 2.04 (1H, dt, J 12.8, 3.3), 2.00 (1H, ddd, J 13.2, 5.4, 2.1), 1.93-1.86 (1H, m), 1.86 - (2H, m), 1.56 (1H, dq, J 13.4, 3.7), 1.44 (1H, qd, J 13.0, 4.0), 1.40-1.28 (3H, s, C19H), 1.06 (3H, d, J 6.7, C21H), 0.77 (3H, s, C18H). ^{13 C NMR (176 MHz, CDCl} 3): δ = 199.9, 163.8, 141.1, 128.0, 123.6, 57.9, 53.2, 53.0, 50.6, 43.6, 39.3, 37.7, 36.9, 36.0, 34.0, 33.9, 27.8, 23.8, 20.6 , 17.8, 16.3, 12.0.

(20 S ) - Aminomethyl - Pregnana -4,6- Dien 3-one

(20 S ) -azidomethyl-pregna-4,6-dien-3-one (99 mg, 0.292 mmol) and triphenylphosphine (106 mg, 0.404 mmol) in THF To the solution was added acetone (300 [mu] l). The reaction mixture was stirred at room temperature for 64 h. The reaction mixture was diluted with ethyl acetate (10 mL) and a 2 M aqueous hydrochloric acid solution (10 mL). The layers were separated and the aqueous phase was basified to pH 11 with 2 M aqueous sodium hydroxide (6.5 mL) and extracted with ethyl acetate (10 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM-MeOH) to give the desired product (28 mg, 30% yield) as off-white powder. _{R f 0.23 (4: 1,} CH 2 Cl 2: MeOH); ^{1 H NMR (700 MHz, CDCl} 3): δ = 6.12-6.07 (2H, m, C6H and C7H), 5.67 (1H, s , C4H), 3.05 (1H, dd, J 12.7, 3.1, C22 H a H _{b), 2.74 (1H, dd} , J 12.7, 8.3, C22H a H b), 2.58 (1H, ddd, J 17.9, 14.5, 5.4, C2 H a H b), 2.46-2.41 (1H, m, C2H a _{H b), 2.18 (1H,} t, J 10.5), 2.05-1.94 (3H, m), 1.90-1.81 (2H, m), 1.68 (1H, td, J 13.9, 5.6), 1.55 (1H, dq, J 13.4, 3.4), 1.45-1.17 (9H, m), 1.20 (3H, unclear d, J 6.7, C21H), 1.11 (3H, s, C18H), 0.78 (3H, s, C19H). ¹³ C NMR (140 MHz, CDCl ₃ ):? = 199.5, 163.6, 140.8, 128.0, 123.7, 53.2, 52.8, 50.6, 45.3, 43.6, 39.3, 37.6, 36.0, 36.0, 35.1, 34.0, 33.9, 27.8, 23.7 , 20.7, 17.3, 16.3.

Example  35 - (20 R ) -20- (1- Cyanomethyl ) - Pregnana -4,6- Dien 3-one

(20 S ) -20- Bromomethyl -4- Preganen 3-one

To a solution of (20 S ) -hydroxymethyl-4-prenen-3-one (50 g, 0.15 mol) in CH ₂ Cl ₂ (350 mL) at 0 ° C triphenylphosphine (43.6 g, Was added. N -Bromosuccinimide (29.6 g, 0.17 mol) was added in portions and the reaction mixture was stirred at 18 &lt; 0 &gt; C. After 18 h, the reaction mixture was cooled to 0 C and triphenylphosphine (19.8 g, 0.08 mol) followed by N -bromosuccinimide (13.5 g, 0.08 mol) was added in portions. The mixture was warmed to 18 &lt; 0 &gt; C. After 2 h, the reaction mixture was washed with water (350 mL) and the aqueous phase was extracted with CH ₂ Cl ₂ (350 mL). The combined organic phases were washed with 5% aqueous sodium bicarbonate (350 mL) and the aqueous phase was extracted with CH ₂ Cl ₂ (100 mL). The combined organic phases were washed with 5% aqueous sodium chloride (150 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (heptane-EtOAc) to give the desired product (47.1 g, 79%) as a yellow solid. ^{1 H NMR (700 MHz, CDCl} 3): δ = 5.72 (1H, s), 3.50 (1H, dd, J = 9.8, 2.7, C22- C H a H b), 3.35 (1H, dd, J = 9.8 _{, 5.9, C22- CH a H b} ), 2.45-2.32 (3H, m), 2.27 (1H, ddd, J = 14.6, 4.1, 2.5), 2.04-1.98 (2H, m), 1.91-1.82 (2H, (2H, m), 1.72-1.64 (3H, m), 1.56-1.50 (2H, m), 1.43 (1H, qd, J = 13.1,4.1), 1.33-1.27 (1H, d, J = 6.4), 1.09-1.00 (2H, m), 0.94 12.3, 10.9, 4.1), 0.74 (3H, s); ^{13 C NMR (176 MHz, CDCl} 3): δ = 197.5, 169.3, 121.8, 53.5, 51.6, 51.6, 41.4, 40.4, 37.3, 36.5, 35.7, 33.6, 33.6, 31.9, 30.8, 29.9, 25.5, 22.0, 18.9 , 16.6, 15.3, 10.3.

(20 R ) - Cyanomethyl -4- Preganen 3-one

The (20 S), potassium cyanide (7.5 g, 114 mmol) to a suspension of methyl 4-bromo--20- presence geunen 3-one (15 g, 38.1 mmol) in DMF (225 mL) was added. The suspension was stirred at 80 &lt; 0 &gt; C for 41 h and then cooled to room temperature. EtOAc (250 mL) and water (500 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 250 mL) and the combined organic phases were washed with 5% aqueous NaCl (250 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (heptane / EtOAc) to give the desired product (9.7 g, 75%) as a white solid. _{δH (700 MHz, CDCl 3)} ; 5.73 (1H, s, C4- C H), 2.45-2.32 (4H, m), 2.27 (1H, ddd, J = 14.6, 4.2, 2.7), 2.24 (1H, dd, J = 16.8, 7.1), 2.04 (2H, m), 1.43 (2H, m), 1.89-1.78 (3H, m), 1.72-1.65 (2H, m), 0.94 (1H, ddd, J = 12.3, 10.7, 4.1), 0.74 (3H, s), 1.17 (3H, s); _{δC (176 MHz, CDCl 3)} ; 199.5, 171.2, 123.9, 118.9, 55.7, 54.7, 53.6, 42.5, 39.2, 38.5, 35.7, 35.6, 34.0, 33.6, 32.8, 31.9, 28.0, 24.8, 24.1, 20.9, 19.3, 17.4, 12.1.

(20 R ) - Cyanomethyl -4,6- Pragnanien 3-one

Toluene (36 mL) and acetic acid (0.15 mL) of (20 R) - cyano-4-pre geunen 3-one To a suspension of p (9.1 g, 26.8 mmol) - chloranil (7.2 g, 29.5 mmol) Was added. The mixture was heated at reflux for 90 minutes and then allowed to cool to room temperature. The suspension was filtered while washing with toluene (25 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (heptane / EtOAc). The material was then dissolved in acetone (35 mL) and methanol (23 mL) and 0.5 M aqueous NaOH (200 mL) was added dropwise. Water (100 mL) was added and the resulting solid was filtered while washing with water (2 x 50 mL) and 2: 1 acetone: water (2 x 20 mL). The solid was dried in vacuo to give the desired product (5.4 g, 60%) as a light brown solid. _{δH (700 MHz, CDCl 3)} ; 6.11 (2H, s), 5.67 (1H, s), 2.57 (1H, ddd, J = 18.0, 14.4, 5.4), 2.45-2.42 (1H, m), 2.37 (1H, dd, J = 16.7, 3.7) , 2.25 (1H, dd, J = 16.7, 7.2), 2.01 (1H, t, J = 10.4), 2.03 (1H, dt, J = 12.8, 3.3), 2.00 (1H, ddd, J = 13.2, 5.4, 2.1), 1.96-1.91 (1H, m ), 1.88-1.81 (1H, m), 1.74-1.70 (1H, m), 1.58 (1H, dq, J = 13.4, 3.6), 1.44 (1H, qd, J = 4.4, 3.9), 1.36-1.20 (7H, m), 1.18 (3H, d, J = 6.7), 1.11 (3H, s), 0.79 (3H, s); _{δC (176 MHz, CDCl 3)} ; 199.6, 163.67, 140.8, 128.1, 123.7, 118.8, 54.6, 53.2, 50.5, 43.5, 39.1, 37.6, 36.0, 33.9, 33.9, 33.5, 28.0, 24.8, 23.6, 20.6, 19.3, 16.3, 12.0.

Example  36 - (20 S ) - ( N - benzyl ) Aminomethyl - Pregnana -4,6- Dien 3-one

(98 S , 0.30 mmol) and benzylamine (21 L, 0.30 mmol) were dissolved in 1,2-dichloroethane (1.0 mL ). Sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added. The reaction mixture was stirred at 20 &lt; 0 &gt; C for 2 h and then quenched with aqueous sodium bicarbonate solution (5%, 2 mL). The mixture was diluted with EtOAc (10 mL) and water (5 mL). The aqueous phase was separated and extracted with EtOAc (2 x 5 mL). The combined organic phases were concentrated in vacuo. The residue was purified by silica column chromatography (heptane -EtOAc) (20 S) - (N-benzyl) aminomethyl-beige powder, the program regeuna-4,6-dien-3-one (51 mg, 41 % Yield). R _f 0.15 (EtOAc); ^{1 H NMR (500 MHz, CDCl} 3): δ = 7.34 (4H, d, J 4.5, Bn-CH), 7.29-7.23 (1H, m, Bn-CH), 6.15 (1H, d, J 10.2, C6 ), 6.11 (1H, dd, J 9.6, 2.0, C7H), 5.68 (1H, s, C4H), 3.84 (1H, d, J 13.1, Bn-C H a H b), 3.75 (1H, d, J _{13.1, Bn-CH a H b} ), 2.69 (1H, dd, J 11.6, 3.0, C22 H a H b), 2.58 (1H, ddd, J 17.2, 14.5, 5.3, C2 H a H b), 2.44 ( 1H, dd, J 17.4, 4.4 , C2H a H b), 2.35 (1H, dd, J 11.5, 8.3, C22H a H b), 2.20 (1H, t, J 10.7, H8), 2.07 (1H, dt, J 12.6, 3.0), 2.04-1.97 ( 1H, m, C1 H a H b), 1.92-1.68 (3H, m), 1.68-1.60 (1H, m, C20H), 1.60-1.52 (1H, m), 3H, s, C 18 H), 1.04 (3H, d, J 6.6, C 21 H), 0.78 (3H, s, C 19 H), 1.44 (1 H, qd, J 12.8, 3.9), 1.40-1.18 . ^{13 C NMR (126 MHz, CDCl} 3): δ = 199.7, 164.0, 141.4, 140.5, 128.4, 128.1, 127.8, 126.9, 123.5, 54.9, 54.2, 54.0, 53.3, 50.7, 43.5, 39.5, 37.7, 36.5, 36.0 , 34.0, 33.9, 27.9, 23.8, 20.7, 17.8, 16.3, 12.0.

Example  37 - N - ((22 E ) -3,2,4- Dioxo -4,6,22- Colatrien -24-yl) Of cyclopropylsulfonamide  synthesis

To a solution of (22 E ) -3-oxo-4,6,22-collatriene-24-oic acid (2.00 g, 5.43 mmol) in CH ₂ Cl ₂ (40 mL) was added EDCI (1.69 g, 10.9 mmol) DMAP (1.33 g, 10.9 mmol) was added. Cyclopropanesulfonamide (1.97 g, 16.3 mmol) was added and the reaction mixture was stirred at room temperature for 22 h. Water (25 mL) was added and the layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 x 25 mL) and the combined organic layers were washed with 2 M aqueous HCl (20 mL), 10% aqueous NaCl (10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-10% acetone in toluene) to give the desired product (1.68 g, 66%) as a off-white solid. _{δH (400 MHz, CDCl 3)} ; 8.90 (1H, s, N H ), 6.95 (1H, dd, J 15.5, 9.0, C23-C H), 6.11 (2H, brs, C6-C H and C7-C H), 5.86 ( 1H, dd, J 15.5, 0.5, C22-C H), 5.68 (1H, s, C4-C H), 3.00 (1H, dddd, J 12.8, 9.5, 8.1, 4.8, SO 2 C H), 2.64 (1H, ddd, J 18.1, 14.4, 5.4, C2 -C H a H b), 2.51-2.41 (1H, m, C2-CH a H b), 2.40-2.28 (1H, m), 2.25-2.15 (1H, m), M), 1.12 (3H, m), 1.63-1.52 (1H, m), 2.01-1.96 (2H, m), 1.85-1.64 _{, C19-C H 3),} 0.80 (3H, s, C18-C H 3); _{δC (100 MHz, CDCl 3)} ; 16.0, 164.2, 164.1, 155.5, 141.3, 127.9, 123.6, 119.4, 54.7, 53.2, 50.6, 43.8, 39.8, 39.3, 37.8, 36.1, 33.9, 33.9, 31.5, 28.1, 23.7, 20.6, 19.1, 16.3, 12.2, 6.3, 6.3.

Example  38 - N - ((22 E ) -3,2,4- Dioxo -4,6,22- Colatrien -24-yl) -4- ( Trifluoromethoxy ) Benzenesulfonamide

To a solution of (22 E ) -3-oxo-4,6,22-collatriene-24-oic acid (2.00 g, 5.43 mmol) in CH ₂ Cl ₂ (40 mL) was added EDCI (1.69 g, 10.9 mmol) DMAP (1.33 g, 10.9 mmol) was added. 4- (Trifluoromethoxy) benzenesulfonamide (3.93 g, 16.3 mmol) was added and the reaction mixture was stirred at room temperature for 22 h. Water (25 mL) was added and the layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 x 25 mL) and the combined organic layers were washed with 2 M aqueous HCl (20 mL), 10% aqueous NaCl (10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was used in the next step without purification. A portion was purified by column chromatography on silica gel (0-50% EtOAc in heptane) to give the desired product as a off-white solid. [delta] H (400 MHz, MeOD); (2H, m, ArH), 6.82 (1H, dd, J 15.4, 9.0, C23-C H ), 6.20 (1H, brdd, J 9.8, 1.4, C6-C H), 6.15 ( 1H, dd, J 9.9, 1.4, C7-C H), 5.82 (1H, dd, J 15.4, 0.7, C22-C H), 5.64 (1H, s, C4-C H ), 2.62 (1H, ddd, J 18.2, 14.5, 5.4, C2-C H a H b), 2.42-2.20 (3H, m), 2.12-1.98 (2H, m), 1.88-1.63 (3H, m) , 1.63-1.55 (1H, m), 1.49 (1H, dd, J 12.6, 3.8), 1.40-1.18 (7H, m), 1.14 (3H, s, C19-C H 3), 1.08 (3H, d, _{J 6.6, C21-C H 3} ), 0.81 (3H, s, C18-C H 3); [delta] C (100 MHz, MeOD); (Q, J 254), 121.9, 120.6, 56.0, 54.6, 52.2, 44.9, 40.9, 40.6, 39.1, 37.4, 35.0, 34.7, 30.2, 29.0, 24.7, 21.7, 19.5, 16.6, 12.5.

Example  39 - (20 S ) -20- (5- Tosyl tetrazole -1 day) methyl - Pregnana -4,6- Dien 3-one

CH ₂ Cl ₂ (5 mL) of (20 S) - O map methyl-phe regeuna 4,6-diene-3-one in solution of p (500 mg, 1.41 mmol) - toluenesulfonyl cyanide (282 mg , 1.55 mmol). Copper (I) trifluoromethanesulfonate benzene complex (71 mg, 0.141 mmol) was added and the mixture was stirred at room temperature for 18 h. Toluene (5 mL) added with p -toluenesulfonyl cyanide (128 mg, 0.708 mmol) and copper (I) trifluoromethane sulfonate benzene complex (71 mg, 0.141 mmol) was added and the mixture was stirred at 24 h Gt; 60 C. &lt; / RTI &gt; Water (10 mL) and CH ₂ Cl ₂ (30 mL) were added and the layers were separated. The organic layer was washed with 10% aqueous _{Na 2 S 2 O 3/2} % aqueous _{NaHCO 3 (2 x 20 mL)} , 10% aqueous NaCl (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc in heptane) to give the desired product (381 mg, 50%) as a light yellow solid. _{δH (400 MHz, CDCl 3)} ; 8.03-7.97 (2H, m, ArH) , 7.46 (2H, m, ArH), 6.14 (2H, brs, C6-C H and C7-C H), 5.69 ( 1H, s, C4-C H), 4.80 (1H, dd, J 13.4, 3.9, C22-C H a H b), 4.45 (1H, dd, J 13.4, 10.5, C22-CH a H b), 2.26-2.53 (1H, m), 2.51 (3H _{, s, ArC H 3),} 2.49-2.28 (2H, m), 2.24 (1H, appt, J, 10.5), 2.13-1.97 (2H, m), 1.96-1.87 (1H, m), 1.79-1.63 ( 2H, m), 1.53-1.18 (8H , m), 1.13 (3H, s, C19-C H 3), 0.89 (3H, d, J 6.6, C21-C H 3), 0.86 (3H, s, C18 -C H _{3); δC (100 MHz, CDCl 3)} ; 37.8, 37.6, 36.0, 33.9, 33.9, 31.9, 27.5, 23.8, 22.7, 21.9, 20.6, 16.5, 16.3, 12.0.

Example  40 - 23-carboxy-3-oxo-4,6- Cola dien -24-oic acid dimethyl ester

23-carboxy-3-oxo-4- Collen -24-oic acid dimethyl ester

Toluene (150 mL) of (20 S) -20- bromomethyl-4 frame geunen 3-one (15 g, 38.1 mmol), tetrabutylammonium bromide (1.2 g, 3.8 mmol), and potassium carbonate (26.3 g, 191 mmol) in THF (20 mL) was added dimethyl malonate (13.1 mL, 114 mmol) and the reaction mixture was stirred at 80 &lt; 0 &gt; C for 91 h. The reaction mixture was then cooled to room temperature and poured into water (150 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with 5% aqueous sodium chloride (100 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (heptane-EtOAc) to give the desired product (14.8 g, 87%) as a yellow solid. ^{1 H NMR (700 MHz, CDCl} 3): δ = 5.72 (1H, s), 3.75 (3H, s), 3.72 (3H, s), 3.48 (1H, dd, J = 11.0, 4.0), 2.44-2.36 (2H, m), 2.33 (1H, dt, J = 17.0, 3.6), 2.27 (1H, ddd, J = 14.6, 4.1, 2.4), 2.18 (2H, m), 1.95-1.89 (1H, m), 1.85-1.82 (1H, m), 1.71-1.67 (1H, m), 1.64-1.60 m), 0.93 (3H, m), 1.37-1.30 (2H, m), 1.19-1.09 d, J = 6.5), 0.70 (3H, s); ^{13 C NMR (176 MHz, CDCl} 3): δ = 199.6, 171.5, 170.4, 170.0, 123.8, 56.3, 55.8, 53.7, 52.6, 52.4, 49.4, 42.5, 39.6, 38.6, 35.7, 35.6, 35.1, 34.3, 34.0 , 32.9, 32.0, 28.0, 24.1, 21.0, 18.1, 17.4, 11.9.

23-carboxy-3-oxo-4,6- Cola dien -24-oic acid dimethyl ester

23-Carboxy-3-oxo-4-cholene-24-oic acid dimethyl ester (14.5 g, 32.7 mmol) was suspended in toluene (60 mL) and acetic acid (0.19 mL, 3.3 mmol). p -Chloranyl (8.8 g, 35.9 mmol) was added and the mixture was stirred at reflux for 65 min. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with toluene (45 mL) and the filtrate was concentrated under reduced pressure. The residue (21.6 g) was used without further purification. A small portion was purified by column chromatography on silica gel (heptane-EtOAc) to give the product. ^{1 H NMR (700 MHz, CDCl} 3): δ = 6.12 (1H, d, J = 10.8), 6.08 (1H, dd, J = 9.8, 2.2), 5.65 (1H, s), 3.74 (3H, s) , 3.71 (3H, s), 3.47 (1H, dd, J = 11.0, 3.9), 2.58 (1H, dd, J = 14.3, (1H, m), 2.21-2.15 (2H, m), 2.05-1.92 (3H, m), 1.83-1.77 (1H, m), 1.69 (1H, td, J = 13.9, 5.2), 1.55-1.34 5H, m), 1.31-1.11 (5H, m), 1.10 (3H, s), 0.93 (3H, d, J = 6.3), 0.73 (3H, s); ¹³ C NMR (176 MHz, CDCl ₃ ):? = 199.6, 170.4, 170.0, 163.9, 141.4, 127.8, 123.5, 56.1, 53.4, 52.6, 52.4, 50.6, 49.4, 43.5, 39.5, 37.7, 36.0, 35.1, 34.3 , 33.9, 33.9, 28.0, 23.7, 20.6, 18.1, 16.3, 11.9.

Example  41- Example  50 - Additional epoxidation reaction

Example  41 - ( 6β , 7β , 20 S ) -6,7-epoxy-20- Hydroxymethyl - Pregnana -4-en-3-one (20 S ) -20- Hydroxymethyl - Pregnana -4,6- Dien &Lt; / RTI &gt; epoxide

(20 S ) - (20) -hydroxymethyl-pregna-4,6-dien-3-one (188 mg, 0.57 mmol) was dissolved in formic acid (3.4 mL) and the solution was protected from light. t -Butyl hypochlorite (57 [mu] L, 0.50 mmol) was added. The reaction mixture was stirred at 18 [deg.] C for 15 min and then quenched by addition of sodium bisulfite aqueous solution (10%, 0.60 mL). The mixture was concentrated in vacuo and then diluted with CH ₂ Cl _{2 (} 5 mL) and water (5 mL). The aqueous phase was separated and extracted with CH ₂ Cl ₂ (2 × 5 mL). The combined organic phases were washed with aqueous sodium bicarbonate (5%, 10 mL). The sodium bicarbonate phase was diluted with aqueous sodium chloride solution (5%, 10 mL) and re-extracted with CH ₂ Cl ₂ (2 x 10 mL). All organic phases were combined and concentrated in vacuo to afford the intermediate as a yellow viscous oil (207 mg, R _f : 0.44 (3: 2 heptane: EtOAc)) which was used in the next step without further purification. The residue was dissolved in ethanol (5.0 mL) and a solution of potassium carbonate (132 mg, 0.955 mmol) in water (1.4 mL) was added. The reaction mixture was heated at reflux for 15 min, then cooled to 40 &lt; 0 &gt; C and acetic acid (80 [mu] l) was added. The reaction mixture was diluted with water (5 mL) and CH ₂ Cl ₂ (10 mL), the aqueous phase was separated and extracted with CH ₂ Cl ₂ (2 × 10 mL). The organic phases were combined and concentrated in vacuo. The unrefined product (220 mg) was purified by flash chromatography on silica gel (heptane-EtOAc) to give (6β, 7β, 20S) -6,7-epoxy-20-hydroxymethyl-pregna- 3-one as a white powder (69 mg, 35% yield). _Rf : 0.18 (3: 2, heptane: EtOAc); ^{1 H NMR (500 MHz, CDCl} 3): δ = 6.14 (1H, s, C4H), 3.63 (1H, dd, J 10.5, 3.1, C22H), 3.38 (1H, dd, J 10.5, 6.8, C22H), 3.35 (2H, br. s, C6H and C7H), 2.54 (1H, ddd , J 17.5, 15.1, 5.0, C2H), 2.40 (1H, br d, J 17.5, C2H), 2.02 (1H, dt, J 12.8 , 3.3), 1.99-1.83 (4H, m), 1.76 (1H, br. s, O H), 1.64 (1H, td, J 13.9, 4.3), 1.65-1.54 (1H, m), 1.51 (1H, dq, J 13.5, 3.1), 1.47-1.23 (5H, m), 1.23-1.14 (1H, unclear m), 1.20 (3H, unclear s, C19H), 1.10-1.02 1.05 (3H, unclear d, J 6.7, C21H), 0.75 (3H, s, C18H). ¹³ C NMR (100 MHz, CDCl ₃ ):? = 198.5, 163.3, 129.3, 67.6, 59.3, 55.7, 52.5, 52.2, 51.6, 43.4, 39.2, 38.6, 36.6, 36.1, 35.5, 34.1, 27.6, 23.9, 21.2 , 16.8, 16.7, 11.9.

Example  42 - ( 6β , 7β , 20 S ) -6,7-epoxy-20- Bromomethyl - Pregnana -4-en-3-one (20 S ) -20- (bromomethyl) -pregna-4,6-dien-3-one

(20 S ) -20- (bromomethyl) -pregna-4,6-dien-3-one (202 mg, 0.517 mmol) was dissolved in formic acid (3.6 mL) and the solution was protected from light. t -Butyl hypochlorite (62 [mu] L, 0.548 mmol) was added. The reaction mixture was stirred at 18 [deg.] C for 15 min and then quenched by addition of sodium bisulfite aqueous solution (10%, 0.66 mL). The reaction mixture was diluted with CH ₂ Cl ₂ (5 mL) and water (5 mL). The organic phase was separated and washed with aqueous sodium bicarbonate solution (5%, 10 mL). The sodium bicarbonate phase was re-extracted with CH ₂ Cl ₂ (2 × 5 mL). The combined organic phases were concentrated in vacuo to provide the intermediate as a yellow viscous oil (287 mg, _Rf : 0.49 (3: 2, heptane: EtOAc)) which was used in the next step without further purification. The residue was dissolved in ethanol (6.0 mL) and a solution of potassium carbonate (146 mg, 1.06 mmol) in water (1.4 mL) was added. The reaction mixture was heated at reflux for 15 min, then cooled to 40 &lt; 0 &gt; C and acetic acid (112 [mu] l) was added. The reaction mixture was diluted with water (5 mL) and CH ₂ Cl ₂ (10 mL) and the aqueous phase was separated and extracted with CH ₂ Cl ₂ (2 × 5 mL). The combined organic phases were concentrated in vacuo. The crude product (244 mg) was purified by flash chromatography on silica gel (heptane-EtOAc) to give (6β, 7β, 20S) -6,7- 3-one as a colorless oil, which solidified to a white solid (152 mg, 72% yield). _Rf : 0.50 (3: 2, heptane: EtOAc); ^{1 H NMR (500 MHz, CDCl} 3): δ = 6.14 (1H, s, C4H), 3.49 (1H, dd, J 9.8, 2.6, C22H), 3.37 (1H, obscure m, C22H), 3.35 (2H (M, C6H and C7H), 2.58 (1H, ddd, J 17.5, 15.0, 5.0, C2H), 2.40 (1H, br d, J 17.5, C2H), 2.02-1.86 (1H, m), 1.64 (1H, td, J 14.4, 4.4), 1.52 (1H, dq, J 13.7, 3.6), 1.47-1.21 (1H, unclear m), 1.09 (3H, unclear d, J 6.5, C21H), 0.76 (3H, s, C18H). ¹³ C NMR (100 MHz, CDCl ₃ ):? = 198.2, 162.9, 129.4, 59.1, 55.7, 53.4, 52.5, 51.5, 43.4, 43.3, 39.0, 37.5, 36.6, 36.1, 35.6, 34.1, , 18.6, 16.8, 12.2.

Example  43 - (20 S ) - Methanesulfonyloxymethyl -6,7-? -Epoxy-4- Preganen -3- On  For forming (20 S ) -20- (1-mesyloxymethyl) -pregna-4,6-dien-3-one

To a solution of (20S) -20- (1-mesyloxymethyl) -pregna-4,6-dien-3-one (200 mg, 0.5 mmol) in formic acid (3.6 mL) under argon was added t BuOCl 0.52 mmol) and the reaction mixture was stirred at 18 &lt; 0 &gt; C. After 30 min, the reaction was quenched with aqueous 10% NaHSO ₃ (0.66 mL) and stirred for 10 min. The reaction mixture was diluted with CH ₂ Cl ₂ (100 mL) and washed with aqueous 5% NaHCO ₃ (2 x 25 mL) and aqueous 5% NaCl (25 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to provide 186 mg of crude material. The crude material in 18 ℃ temperature is dissolved in EtOH (3.7 mL) was added _{K 2 CO 3 (105mg, 0.76} mmol) and H ₂ O. After 30 min, the reaction mixture was heated to 80 &lt; 0 &gt; C for 2 h, then cooled to 18 &lt; 0 &gt; C and quenched with a mixture of 1: 4 AcOH: EtOH (0.1 mL). The organic solvent was removed in vacuo and the residue was dissolved in CH ₂ Cl ₂ (15 mL). The organic phase was washed with aqueous 5% NaCl (15 mL) and the aqueous phase was extracted with CH ₂ Cl ₂ (2 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. It provided the methanesulfonyloxymethyl -6,7-epoxy-4-β- presence geunen 3-one (yield: 41%) was purified by column chromatography on silica gel (S 20). _Rf : 0.36 (1: 1, heptane: EtOAc); ^{1 H NMR (700 MHz, CDCl} 3): 6.15 (1H, s, C4H), 4.19 (1H, dd, J 9.4, 3.1 Hz, C22H), 4.02 (1H, dd, J 9.4, 6.4 Hz, C22H) 3.37 (2H, m, C6H, C7H ), 3.01 (3H, s), 2.59 (1H, ddd, J 20.0, 15.1, 5.0 Hz), 2.42 (1H, m), 2.05 - 1.89 (5H, m), 1.87 - M), 1.21 (3H, m), 1.83 (1H, m), 1.66 (1H, td, J 14.5, 4.5 Hz), 1.53 (1H, ddd, J 13.6, 7.1, 3.6 Hz) , 1.10 (3H, d, J 6.6 Hz, C23H), 1.08 (1H, td, J 12.2, 2.9 Hz), 0.77 (3H, s); ^{13 C NMR (175 MHz, CDCl} 3): 198.3, 163.0, 129.4, 74.8, 59.1, 55.7, 52.4, 51.6, 51.5, 43.5, 39.0, 37.2, 36.6, 36.3, 36.1, 35.5, 34.1, 27.5, 23.9, 21.2 , 16.9, 16.8, 11.9.

Example  44 - (20 R ) - Cyanomethyl -6,7-? -Epoxy-4- Preganen -3- On  For forming (20 R ) -20- (1- Cyanomethyl ) - Pregnana -4,6- Dien &Lt; / RTI &gt; epoxide

(1.1 g, 3.2 mmol) was dissolved in formic acid (19.4 mL) and tert -butyl hypochlorite (383 ml) was added to the solution, Mu] L, 3.39 mmol). The reaction mixture was stirred at 18 &lt; 0 &gt; C. After 20 min, the mixture was quenched with sodium bisulfite (3 mL, 10% aqueous solution) and diluted with EtOAc (100 mL), water (100 mL), and sodium chloride solution (50 mL, 5% aqueous solution). The aqueous phase was extracted with EtOAc (50 mL) and the combined organic phases were washed with sodium bicarbonate (3 x 100 mL of 5% aqueous solution) and concentrated in vacuo to provide the intermediate which was used without further purification . The residue was suspended in ethanol (28 mL) and warmed to 40 &lt; 0 &gt; C to dissolve. Potassium carbonate (885 mg, 6.4 mmol) was dissolved in water (7 mL) and added to the ethanolic solution. After 15 min at 18 [deg.] C, TLC indicated complete consumption of the intermediate and the mixture was heated to reflux. After 40 min, the reaction mixture was cooled to 18 &lt; 0 &gt; C and neutralized with 4: 1 ethanol: acetic acid. The mixture was concentrated to ~ 7 mL to remove ethanol and then diluted with dichloromethane (80 mL) and sodium chloride solution (80 mL, 5% aqueous solution). The aqueous phase was re-extracted with CH ₂ Cl ₂ (3 × 30 mL) and the combined organic phases were washed with sodium chloride (30 mL, 5% aqueous solution). The aqueous phase was re-extracted with CH ₂ Cl ₂ (30 mL) and the combined organic phases were concentrated in vacuo. The residue was purified by flash chromatography (heptane -EtOAc) on silica gel (20 R) - cyano-methyl -6,7-epoxy-4-β- presence geunen 3-one (0.55 g, 48%) As colorless syrup. _Rf : 0.29 (3: 2, heptane: EtOAc); ^{1 H NMR (500 MHz, CDCl} 3): δ = 6.17 (1H, d, J 0.7), 3.38 (1H, d, J 3.7), 3.37 (1H, d, J 3.7), 2.61 (1H, ddd, J 17.5, 14.9, 5.0), 2.46-2.41 (1H, m), 2.39 (1H, dd, J 16.7, 3.8), 2.30 (1H, dd, J 16.7, 6.9), 2.04-1.91 (4H, m), 1.88 (1H, m), 1.53 (1H, d, J 13.2, 3.5), 1.50-1.26 (6H, m), 1.23 , J 6.7), 1.10 (1H, td, J 6.0, 3.7), 0.78 (3H, s); ^{13 C NMR (126 MHz, CDCl} 3): δ = 198.2 (C = O), 162.8 (C = CH), 129.4 (C = C H), 118.7 (CN), 59.0, 55.7, 54.4, 52.6, 51.4, 43.5, 39.0, 36.6, 36.1, 35.5, 34.1, 33.4, 27.9, 24.8, 23.8, 21.2, 19.3, 16.8, 11.9.

Example  45 - (20 S ) -20- Acetoxymethyl -6,7- [beta] -epoxy- Pregnana -4-en-3- On  For forming (20 S ) -20- Acetoxymethyl - Pregnana -4,6- Dien &Lt; / RTI &gt; epoxide

(20 S) -20- acetoxymethyl-phe regeuna 4,6-diene-3-one (5 g, 13.5 mmol) was dissolved in formic acid (90 mL) tert-butyl hypochlorite (1.62 mL, 14.3 mmol). The reaction mixture was stirred at 18 &lt; 0 &gt; C. After 20 min, the mixture was quenched with sodium bisulfite (15 mL, 10% aqueous solution) Was diluted with EtOAc (250 mL), water (250 mL), and sodium chloride solution (50 mL, 5% aqueous). The aqueous phase was re-extracted with EtOAc (50 mL) and the combined organic phases were washed with sodium bicarbonate (4 x 250 mL, 5% aqueous) and concentrated in vacuo to provide the intermediate which was used without further purification . The residue was dissolved in ethanol (116 mL) and a solution of potassium carbonate (3.7 g, 27 mmol) in water (29 mL) was added. After 15 min at 18 [deg.] C, TLC indicated complete consumption of the intermediate and the mixture was heated to reflux. After 50 min, the mixture was allowed to cool to 18 [deg.] C and neutralized (to pH 7) with 4: 1 EtOH: AcOH. The mixture was concentrated to ~30 mL to remove ethanol and then diluted with CH ₂ Cl ₂ (80 mL) and sodium chloride (80 mL of 5% aqueous solution). The aqueous phase was re-extracted with CH ₂ Cl ₂ (3 × 50 mL). The combined organic phases were concentrated in vacuo and purified by flash chromatography (heptane -EtOAc) on silica gel (20 S) -20- acetoxymethyl β- -6,7-epoxy-4-en-3-profile regeuna (2.87 g, 54%) as light yellow syrup which solidified upon standing. _Rf : 0.41 (3: 2, heptane: EtOAc); ^{1 H NMR (700 MHz, CDCl} 3): δ = 6.15 (1H, d, J 0.6), 4.09 (1H, dd, J 10.7, 3.5), 3.80 (1H, dd, J 10.7, 7.4), 3.37 (2H , s), 2.59 (1H, ddd, J 17.5, 15.0, 5.0), 2.43-2.40 (1H, m), 2.06 (3H, s), 2.03 (1H, dt, J 12.9, 3.4), 1.98 (1H, t, J 11.6), 1.93-1.90 ( 3H, m), 1.80-1.74 (1H, m), 1.65 (1H, dd, J 7.0, 4.3), 1.52 (1H, dq, J 13.5, 3.6), 1.48- 1.37 (3H, m), 1.34 (1H, qd, J 6.6, 3.8), 1.30-1.25 (1H, m), 1.23-1.19 (1H, m), 1.21 (3H, s), 1.08 (1H, td, J 6.0, 3.6), 1.03 (3H, d, J 6.7), 0.77 (3H, s); ^{13 C NMR (176 MHz, CDCl} 3): δ = 198.4, 171.3, 163.1, 129.3, 69.3, 59.2, 55.7, 52.5, 51.6, 43.5, 39.2, 36.6, 36.1, 35.7, 35.5, 34.1, 27.6, 23.9, 21.3 , 21.0, 17.1, 16.8, 11.9.

Example  46 - ( 6β , 7β , 20 S ) -6,7-epoxy-20- tert - Butyl diphenylsiloxymethyl - Pregnana -4-en-3-one (20 S ) - tert - Butyl diphenylsilyloxymethyl - Pregnana Epoxidation of 4,6-dien-3-one

To a solution of 4,6-dien-3-one regeuna program (230 mg, 0.41 mmol) - tert - - butyl-diphenyl-silyloxy methyl (S 20) in: (1, 15 vol 12) : acetone, H ₂ O TCCA (38 mg, 0.4 eq) was added and the reaction mixture was stirred at 20 &lt; 0 &gt; C. After 3 h, the reaction mixture was filtered, diluted with DCM (25 mL) and washed with 10% w / v aqueous NaHSO ₃ (25 mL) followed by H ₂ O (25 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in EtOH (3.88 mL, 20 vol) at ambient temperature and K ₂ CO ₃ (85 mg, 2 eq) and H ₂ O (0.97 mL, 5 vol) were added. The reaction mixture was heated to 80 &lt; 0 &gt; C. After 2 h, the reaction mixture was cooled to ambient temperature and quenched with a mixture of 1: 4 AcOH: EtOH (0.2 mL). The organic solvent was removed in vacuo and the residue was dissolved in DCM (25 mL). The organic phase was washed with 5% w / v aqueous NaCl (25 mL) and the resulting aqueous phase was extracted with DCM (2 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by column chromatography on silica gel (6β, 7β, 20 S) -20- tert - butyl-diphenyl-silyloxy-6,7 epoxy-phe regeuna 4,6-diene-3-one (68 mg, 29% yield). R _f 0.67 (1: 1, EtOAc: heptane); ^{1 H NMR (500 MHz, CDCl} 3): 7.72-7.68 (4H, m), 7.47-7.39 (6H, m), 6.17 (1H, s), 3.65 (1H, dd, J 9.8, 3.1), 3.45- (1H, m), 2.40 (1H, m), 3.40 (1H, M), 2.01-1.92 (2H, m), 1.90-1.51 (6H, m), 1.42-1.19 (5H, m), 1.23 (3H, s), 1.13 (9H, s), 0.75 (3H, s); ^{13 C NMR (125 MHz, CDCl} 3): 198.4, 163.3, 135.7, 135.6, 134.1, 134.0, 129.5, 129.3, 129.6, 129.5, 68.5, 59.3, 55.8, 52.6, 52.2, 51.7, 43.4, 39.3, 38.9, 36.7 , 36.1, 35.6, 34.1, 27.5, 24.0, 21.3, 19.4, 17.2, 16.9, 11.9.

Example  47 - ( 6β , 7β , 20 S ) -6,7-epoxy-20- Azidomethyl - Pregnana -4-en-3-one (20 S ) -Azidomethyl-pregna-4,6-dien-3-one &lt; / RTI &

Formic acid (4.6 mL) of (20 S) - O map methyl-butyl hypochlorite (90 ㎕, 0.799 mmol) - print regeuna 4,6-diene-3-one To a solution of t (256 mg, 0.754 mmol) Was added. The reaction mixture was stirred at 18 [deg.] C for 15 min and then quenched with aqueous sodium bisulfite solution (10%, 0.84 mL). The mixture was diluted with CH ₂ Cl ₂ (20 mL) and the organic phase was washed with water (10 mL) and aqueous sodium bicarbonate (5%, 10 mL). The organic phase was concentrated in vacuo to provide the intermediate as an orange viscous oil (392 mg, _Rf : 0.48 (3: 2, heptane: EtOAc)), which was used without further purification. The residue was suspended in ethanol (8.6 mL) and a solution of potassium carbonate (219 mg, 1.58 mmol) in water (2.0 mL) was added. The reaction mixture was stirred at 18 [deg.] C for 15 min and then heated at reflux for 20 min. After cooling to 40 &lt; 0 &gt; C, acetic acid (157 [mu] l) was added. The mixture was concentrated in vacuo and diluted with EtOAc (20 mL) and water (20 mL). The organic phase was separated and concentrated in vacuo to a yellow solid (583 mg). The residue was purified by silica column chromatography (heptane -EtOAc) on silica gel (6β, 7β, 20 S) -6,7- epoxy -20- O map-methyl-4-en-3-on-profile regeuna As a pale yellow oil (98 mg, 37% yield). _Rf : 0.23 (4: 1, heptane: EtOAc); ^{1 H NMR (700 MHz, CDCl} 3): δ = 6.15 (1H, s, C4H), 3.40-3.35 (3H, m, C6H, C7H, C22 H a H b), 3.10 (1H, dd, J 11.9, _{7.1, C22H a H b),} 2.59 (1H, ddd, J 20.0, 15.0, 5.1, C2 H a H b), 2.44-2.39 (1H, m, C2H a H b), 2.01 (1H, dt, J 13.0 , 3.4), 1.94-1.89 (3H, m), 1.72-1.62 (3H, m), 1.52 (1H, dq, J 14.0, 3.8), 1.43-1.24 (5H, m), 1.23-1.18 (1H, m, m), 1.21 (3H, unclear s, C18H), 1.10-1.15 (1H, unclear m), 1.06 (3H, d, J 6.7, C21H), 0.76 (3H, s, C19H). ^{13 C NMR (176 MHz, CDCl} 3): δ = 198.4, 163.0, 129.4, 59.2, 57.9, 55.7, 52.9, 52.6, 51.6, 43.5, 39.1, 36.8, 36.6, 36.1, 35.5, 34.1, 27.8, 23.9, 21.2 , 17.7, 16.8, 11.9.

Example  48 - ( 6β , 7β , 20 S ) -6,7-epoxy-20- ( N - Phthalimidomethyl ) - Pregnana Dien-3-one (20 &lt; RTI ID = 0.0 &gt; S ) - ( N - Phthalimidomethyl ) - Pregnana -4,6- Dien &Lt; / RTI &gt; epoxide

(20 S) - (N-methyl phthalimide yimido) program regeuna 4,6-diene-3-one (100 mg, 0.22 mmol) was dissolved in formic acid (1.8 mL) and tert-butyl hypochlorite (27 ㎕ , 0.24 mmol). The reaction mixture was stirred at 23 &lt; 0 &gt; C. After 15 min, the mixture was quenched with 10% w / v aqueous sodium bisulfite (0.33 mL) and diluted with DCM (10 mL). The organic phase was washed with water (2 x 10 mL), 5% w / v aqueous sodium bicarbonate (10 mL), and 5% w / v aqueous sodium chloride (10 mL) and then concentrated in vacuo to provide the intermediate , Which was used without further purification. The residue was suspended in ethanol (2 mL), warmed to 50 &lt; 0 &gt; C and DMF (2 mL) was added. Potassium carbonate (51 mg, 0.37 mmol) dissolved in water (0.5 mL) was added and the mixture was heated to 90 &lt; 0 &gt; C. After 2 h, the reaction mixture was cooled to 23 [deg.] C, diluted with water (10 mL) and extracted with TBME (2 x 20 mL). The combined organic phases were washed with 5% w / v aqueous sodium chloride (10 mL) and concentrated. Purification by (6β, 7β, 20 S) -6,7- epoxy -20-The residue was purified by chromatography (heptane-ethyl acetate) on silica gel (N-phthalimide yimido methyl) -4,6-loop regeuna Dien-3-one (19 mg, 21%) as a white solid. _Rf : 0.57 (1: 1, heptane: ethyl acetate); ^{1 H NMR (500 MHz, CDCl} 3): δ = 7.85 (2H, m), 7.72 (2H, m), 6.16 (1H, s), 3.66 (1H, dd, J 13.3, 3.7), 3.44 (1H, (2H, m), 1.54-1.62 (2H, m), 2.42 (1H, (9H, m), 1.09 (1H, m), 0.91 (3H, d, J6.7), 0.78 (3H, s); ^{13 C NMR (126 MHz, CDCl} 3): δ = 198.4, 168.8, 163.4, 113.9, 132.0, 129.4, 123.3, 59.3, 55.7, 54.4, 52.5, 51.6, 43.8, 43.6, 39.2, 36.6, 36.1, 36.1, 35.5 , 34.1, 27.8, 24.1, 21.2, 17.0, 16.8, 11.9.

Example  49 - ( 6β , 7β , 20 S ) -6,7-epoxy-20- Formyl - Pregnana -4-en-3- On  (20S) -20- ( Ethylene dioxymethyl ) - Pregnana -4,6- Dien &Lt; / RTI &gt; epoxide

To a solution of (20 S ) -20- (ethylenedioxymethyl) -pregna-4,6-dien-3-one (168 mg) in formic acid (3 mL, 18 vol) under argon was added t BuOCl 1.06 eq) and the reaction mixture was stirred at ambient temperature. After 30 min, the reaction was quenched with aqueous 10% NaHSO ₃ (0.55 mL, 3.3 vol) and stirred for 10 min (-ve peroxide test). The reaction mixture was diluted with CH ₂ Cl ₂ (100 mL) and washed with aqueous 5% NaHCO ₃ (2 x 100 mL) and aqueous 5% NaCl (100 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to give a wet residue of 1.76 g. The crude material in 18 ℃ dissolved in EtOH (35 mL) was added _{K 2 CO 3 (912mg, 6.6} mmol) and _{DI H 2 O (8.8 mL)} . After 30 min, the reaction mixture was heated to 80 &lt; 0 &gt; C. After 2 hr, the reaction mixture was cooled to 18 [deg.] C and quenched with a mixture of 1: 4 AcOH: EtOH (1 mL). The organic solvent was removed in vacuo and the residue was dissolved in CH ₂ Cl ₂ (50 mL). The organic phase was washed with aqueous 5% NaCl (50 mL) and the resulting aqueous phase was washed with CH ₂ Cl ₂ (2 x 20 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by column chromatography on silica gel (6β, 7β, 20 S) -6,7- epoxy -20-formyl-4-en-3-on-profile regeuna (76 mg, 49%) the C21-epi Gt; 1: 1 &lt; / RTI &gt; R _f 0.52 (1: 1, EtOAc: heptane); ^{1 H NMR (700 MHz):} 9.60 (0.5H, d, J 3.1), 9.54 (0.5Hz, d, J 5.1), 6.15 (1H, s), 3.37 (2H, m), 2.65-2.55 (1H, m), 2.45-2.35 (2H, m), 2.02-1.88 (4H, m), 1.70-1.25 (9H, m), 1.22 d, J 6.9), 1.13-1.08 (1H, m), 1.07 (1.5H, d, J 6.9), 0.79 (1.5H, s), 0.75 (1.5H, s); ^{13 C NMR (175 MHz, CDCl} 3): 205.4, 204.5, 198.4, 198.3, 162.9, 162.8, 129.4, 59.1, 59.0, 55.7, 55.6, 52.3, 52.1, 51.7, 51.6, 51.5, 50.7, 49.4, 48.7, 43.9 , 43.1, 39.0, 38.0, 36.6, 36.1, 36.0, 35.5, 35.4, 34.1, 34.0, 31.9, 27.0, 26.3, 24.2, 23.5, 21.2, 21.0, 16.9, 16.8, 13.6, 13.4, 12.8, 12.2.

Example  50 - ( 6β , 7β , 20 S ) -6,7-epoxy-20- ( Ethylene dioxymethyl ) - Pregnana -4-en-3-one (20S) -20- ( Ethylene dioxymethyl ) - Pregnana -4,6- Dien &Lt; / RTI &gt; epoxide

To a solution of (20 S ) -20- (ethylenedioxymethyl) -pregna-4,6-dien-3-one (168 mg) in formic acid (3 mL, 18 vol) under argon was added t BuOCl 1.06 eq) and the reaction mixture was stirred at ambient temperature. After 30 min, the reaction was quenched with aqueous 10% NaHSO ₃ (0.55 mL, 3.3 vol) and stirred for 10 min (-ve peroxide test). The reaction mixture was diluted with CH ₂ Cl ₂ (100 mL) and washed with aqueous 5% NaHCO ₃ (2 x 100 mL) and aqueous 5% NaCl (100 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. 99 mg of the resulting crude material was dissolved in dry CH ₂ Cl ₂ (1 mL, 10 vol) and 1,2-bis (trimethylsiloxy) ethane (59 μL, 1 eqv) was added. The reaction mixture was cooled to -78 [deg.] C and TMSOTf (3 [mu] L, 0.05 eqv) was added. After 1 hour the reaction mixture was warmed to 18 &lt; 0 &gt; C and quenched with pyridine (50 [mu] L, 1 vol). The mixture was dissolved in CH ₂ Cl ₂ and washed with water (2 x 20 mL) and aqueous 5% NaCl (2 x 20 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in EtOH (1 mL) at ambient temperature and K ₂ CO ₃ (17 mg, 2 eqv) and DI H ₂ O (0.25 mL) were added. After 30 min, the reaction mixture was heated to 80 &lt; 0 &gt; C. After 2 hr, the reaction mixture was cooled to ambient temperature and quenched with a mixture of 1: 4 AcOH: EtOH (0.1 mL). The organic solvent was removed in vacuo and the residue was dissolved in DCM (25 mL) and washed with aqueous 5% NaCl (20 mL). The aqueous phase was extracted with DCM (2 x 10 mL) and the combined organic phases were dried over Na ₂ SO _4, and concentrated in vacuo. Service program regeuna-4-en-3-one (26 mg, 15%) - was purified by column chromatography (6β, 7β, 20 S) -6,7- epoxy -20- (ethylenedioxy methyl) Respectively. R _f 0.47 (1: 1, EtOAc: heptane); ^{1 H NMR (700 MHz, CDCl} 3): 6.15 (1H, s, C4H), 4.86 (1H, d, J = 2.0), 3.98-3.93 (2H, m), 3.88-3.83 (2H, m), 3.37 (2H, m, 2H), 2.59 (1H, ddd, J = 17.6, 15.0, 5.0), 2.41 (1H, m), 2.04-1.96 (2H, m), 1.35-1.31 (1H, m), 1.28 (1H, m), 1.86-1.82 D, J = 6.7, C21H), 0.75 (3H, s); ^{13 C NMR (175 MHz, CDCl} 3): 198.4, 163.1, 129.3, 105.9, 65.3, 65.1, 59.3, 55.8, 52.2, 52.1, 51.6, 43.7, 39.2, 39.1, 36.6, 36.1, 35.6, 34.1, 27.2, 24.1 , 21.3, 16.8, 11.7, 11.5.

Example  51 - ( 6β , 7β ) -6,7-epoxy-3-oxo-4- Collen -23-carboxy-24-oic acid dimethyl ester of 23-carboxy-3-oxo- Cola dien -24-epoxidation of an oic acid dimethyl ester

To a solution of 23-carboxy-3-oxo-4,6-colladiene-24-oic acid dimethyl ester (1.28 g) in formic acid (23 mL, 18 vol) under argon was added tBuOCl (348 L, 1.06 eq) The mixture was stirred at 18 [deg.] C. After 30 min, the reaction mixture was quenched with aqueous 10% NaHSO ₃ (4.2 mL, 3.3 vol) and stirred for 10 min (-ve peroxide test). The reaction mixture was diluted with CH ₂ Cl ₂ (100 mL) and washed with aqueous 5% NaHCO ₃ (2 x 100 mL) and aqueous 5% NaCl (100 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to give a wet residue of 1.76 g. The unrefined material was dissolved in EtOH (35 mL, 20 vol) at ambient temperature and K ₂ CO ₃ (912 mg, 2 eq) and DI H ₂ O (8.8 mL, 5 vol) were added. After 30 min, the reaction mixture was heated to 80 &lt; 0 &gt; C. After 2 hr, the reaction mixture was cooled to 18 [deg.] C and quenched with a mixture of 1: 4 AcOH: EtOH (1 mL). The organic solvent was removed in vacuo and the residue was dissolved in CH ₂ Cl ₂ (50 mL). The organic phase was washed with aqueous 5% NaCl (50 mL) and re-extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give (6α, 7β) -6-ethyl-7-hydroxy-3-oxo-4-cholene-2,3-carboxy-24-oic acid dimethyl ester . R _f 0.52 (1: 1, EtOAc: heptane); ^{1 H NMR (700 MHz):} 4.22 (1H, t, J 7.1 Hz), 3.76 (3H, s, COO Me), 3.73 (3H, s, COO Me), 3.48 (1H, dd, J 10.9, 3.9 Hz (1H, m), 1.64 (1H, m), 2.59 (1H, ddd, 17.5,15.0,7.0 Hz) td, J 14.4, 4.4 Hz) , 1.53 - 1.25 (8H, m), 1.21 - 1.15 (5H, m), 1.06 (1H, td, J 12.0, 3.6 Hz), 0.94 (3H, d, J 6.4 Hz) , 0.73 (3H, s); ^{13 C NMR (175 MHz, CDCl} 3): 198.4, 170.6, 170.0, 163.2, 129.3, 59.2, 56.1, 55.7, 52.7, 52.6, 52.5, 51.6, 49.4, 43.5, 39.3, 36.6, 36.1, 35.5, 35.1, 34.3 , 34.1, 28.0, 23.8, 21.3, 18.1, 16.8, 11.8.

Example  52- Example  54 - ( 5β , 6α ) -6-ethyl-3,7- Dioxo -Cholan-23-carboxy-24-oic acid dimethyl ester (precursor of OCA)

Example  52 - ( 6α , 7β ) -6-ethyl-7- Hydroxy -3-oxo-4- Collen -2,3-carboxy-24-oic acid dimethyl ester

To a solution of ZnCl ₂ (0.5 M in THF, 2.1 mL, 0.6 eq) in THF (2.7 mL, 4 vol) at -15 ° C under argon was added EtMgBr (1 M in TBME, 2.1 mL, 1.8 eq) . CuCl (12 mg, 0.05 eq) was added in one portion and the suspension was stirred for 10 min. Oxo-4-cholene-23-carboxy-24-oic acid dimethyl ester (535 mg) was dissolved in THF (2.2 mL, 4 vol) The mixture was stirred for 90 min. Saturated NH ₄ Cl (aq, 1.5 mL, 2.5 vol) was added dropwise and the mixture was allowed to warm to room temperature. The reaction mixture was diluted with EtOAc (25 mL) and washed with saturated NH ₄ Cl (aq., 2 x 20 mL) and water (2 x 20 mL). The organic phase was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to give (6α, 7β) -6-ethyl-7-hydroxy-3- ). _Rf 0.43 (1: 1, EtOAc: heptane); ^{1 H NMR (700 MHz):} 5.83 (1H, s), 4.20 (1H, m), 3.75 (3H, s, COO Me), 3.72 (3H, s, COO Me), 3.48 (1H, dd, J 11.0 , 3.9 Hz), 3.13 (1H, td, J 9.8,4.4 Hz), 2.40-2.28 (3H, m), 2.21-2.15 (1H, m), 2.05-1.90 (5H, m), 1.83 ), 1.73 (1H, td, J 13.2, 4.8 Hz), 1.65-1.53 (4H, m), 1.50-1.33 (4H, m), 1.19 , m), 1.01 (1H, td, J 12.2, 3.8 Hz), 0.94 (3H, d, J 6.5 Hz), 0.91 (3H, t, J 7.4 Hz), 0.72 (3H, s); ^{13 C NMR (175 MHz, CDCl} 3): 199.8, 170.4, 170.0, 169.5, 122.6, 61.5, 61.3, 60.4, 55.5, 55.3, 52.6, 52.4, 49.7, 49.4, 48.2, 43.7, 43.0, 39.5, 38.5, 35.3 , 35.1, 34.2, 33.4, 28.5, 26.8, 21.5, 18.8, 18.3, 12.1.

Example  53 - ( 5β , 6α , 7β ) -6-ethyl-7- Hydroxy -3-oxo-cholan-23-carboxy-24-oic acid dimethyl ester

(6α, 7β) -6-ethyl-7-hydroxy-3-oxo-4-cholene-23-carboxy-24-oic acid dimethyl ester (0.75 mL, 3 vol) and MeCN (250 mg) was evacuated and purged with argon three times and then cooled to 0 &lt; 0 &gt; C. 10% Pd / C was added in one portion, the flask evacuated and charged with argon three times. The flask was evacuated, charged three times with hydrogen and stirred under an atmosphere of hydrogen for 18 hrs. The flask was evacuated, purged with argon three times, the suspension was filtered through a PTFE HPLC filter cartridge, and the cake was washed with TBME (2 x 20 mL). The filtrate was washed with water (2 x 20 mL) and 5% NaCl (aqueous, 20 mL), dried over Na ₂ SO _4, and concentrated in vacuo. (5β, 6β, 7α) -6-ethyl-7-hydroxy-3-oxo-cholan-23-carboxy-24-oic acid dimethyl ester (70 mg, 28%) as a colorless solid Respectively. R _f 0.53 (1: 1, EtOAc: ^{heptane), 1 H NMR (700 MHz} ): 4.20 (1H, m), 3.75 (3H, s, COO Me), 3.72 (3H, s, COO Me), 3.48 (1H, dd, J 11.0, 4.0 Hz), 3.23 (1H, td, J 9.9, 4.8 Hz). (2H, m), 2.31-2.33 (2H, m), 2.21-2.17 (3H, m), 2.12-2.03 (2H, m), 1.98-1.77 ), 1.24 (1H, m), 1.20 (1H, td, J 13.2, 4.2 Hz), 1.10 (1H, q, J 9.7 Hz), 1.04 (3H, d, J 6.5 Hz), 0.88 (3H, t, J 7.0 Hz), 0.70 (3H, s); ^{13 C NMR (175 MHz, CDCl} 3): 212.1, 170.4, 170.0, 75.0, 56.0, 55.5, 52.6, 52.4, 49.4, 45.1, 44.0, 43.7, 43.5, 40.1, 39.5, 37.7, 37.0, 36.6, 35.2, 34.8 , 34.3, 28.5, 26.8, 22.6, 21.9, 20.7, 18.3, 12.2, 11.1.

Example  54 - ( 5β , 6α ) -6-ethyl-3,7- Dioxo -Cholan-23-carboxy-24-oic acid dimethyl ester (precursor of OCA)

(5β, 6α, 7β) -6-ethyl-7-hydroxy-3-oxo-cholan-23-carboxy-24-oic acid dimethyl ester (95 mg) in CH ₂ Cl ₂ (2.4 mL, 25 vol) (DMP, 98 mg, 1.2 eq) was added to a solution of &lt; RTI ID = 0.0 &gt; After 60 min, an additional portion of DMP (50 mg, 0.6 eq) was added. After an additional 60 min, an additional portion of DMP (50 mg, 0.6 eq) was added. After 30 min, the mixture was partitioned between EtOAc (10 mL) and 10% Na ₂ S ₂ O ₃ /2% NaHCO ₃ (95 mL) and stirred for 30 min. The aqueous phase was extracted with EtOAc (10 mL) and the combined organic phases were washed with 1 M NaOH (aq., 2 x 10 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by column chromatography on silica gel gave (5β, 6α) -6-ethyl-3,7-dioxo-cholan-23-carboxy-24-oic acid dimethyl ester (67%) as a white crystalline solid. R _f 0.36 (1: 1, EtOAc: heptane);

^{1 H NMR (700 MHz, CDCl} 3): δ = 3.75 (3H, s), 3.73 (3H, s), 3.47 (1H, dd, J = 11.0, 4.0), 2.74 (1H, dd, J = 11.0, M), 1.89-1.80 (2H, m), 1.72-1.46 (6H, m), 2.09-1.96 1.39 - 1.34 (1H, m), 1.33 (3H, s), 1.32-1.23 (2H, m), 1.21-1.33 (2H, m), 1.10-1.07 ), 0.94 (3H, d, J = 6.5), 0.81 (3H, t, J = 7.4), 0.68 (3H, s); ^{13 C NMR (176 MHz, CDCl} 3): δ = 212.1, 210.5, 170.3, 170.0, 55.3, 52.6, 52.4, 52.3, 52.2, 49.9, 49.34, 48.8, 43.7, 42.7, 38.8, 38.3, 36.6, 35.9, 35.4 , 35.1, 34.2, 28.2, 24.5, 22.9, 22.2, 18.6, 18.2, 12.1, 11.8.

Example  55- Example  58 - ( 5β , 6α ) -6-ethyl-3,7- Dioxo -Cholan-23-carboxy-24-oic acid dimethyl ester

Example  55 - ( 3α , 5β , 6α ) -6-ethyl-3- Hydroxy -7-oxo-cholan-23-carboxy-24-oic acid dimethyl ester.

To a suspension of NaBH ₄ (27 mg, 1 eq) in IPA (2.3 mL) was added a solution of (5β, 6α) -6-ethyl-3,7-dioxo-cholan- A solution of 24-oxo-dimethyl ester (350 mg) was added at -20 &lt; 0 &gt; C over 10 min. After 30 min, 0.7 MH ₂ SO ₄ (2.5 mL) was added dropwise over 10 min and the solution was warmed to 18 ° C. The solution was diluted with EtOAc (50 mL) and the organic phase was washed with water (3 x 50 mL) and 5% aqueous NaCl (50 mL). The organic phase was dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give (3?, 5?, 6?) -6-ethyl-3-hydroxy-7-oxo-cholan-23-carboxy-24-oic acid dimethyl ester (298 mg, 85%).

^{1 H NMR (700 MHz, CDCl} 3): δ = 3.74 (3H, s), 3.72 (3H, s), 3.52 (1H, m), 3.47 (1H, dd, J = 11.0, 4.0), 2.69 (1H (2H, m), 1.85-1.68 (7H, m), 1.50-7.28 (2H, m) (3H, d, J = 6.5), 0.80 (3H, t, J), 1.43 (4H, m) = 7.4), 0.64 (3H, s); ¹³ C NMR (176 MHz, CDCl ₃ ):? = 212.8, 170.4, 170.0, 71.1, 55.3, 52.6, 52.4, 52.0, 50.7, 49.9, 49.4, 49.0, 43.7, 42.7, 39.0, 35.7, 35.1, , 31.8, 29.8, 28.3, 24.6, 23.5, 21.8, 18.8, 18.2, 12.0, 12.0.

Example  56 - ( 3α , 5β , 6α , 7α ) -6-ethyl-3,7- Dihydroxy -Cholan-23-carboxy-24-oic acid dimethyl ester.

To a solution of (3α, 5β, 6α) -6-ethyl-3-hydroxy-7-oxo-cholan-23-carboxy-24-oic acid dimethyl ester in THF (20 mL, 100 vol) of _{NaBH 4 (154 mg, 10 eq} ) at 0 ℃ to a solution of (200 mg) was added in three divided time. The solution was stirred for 1 h and allowed to warm to 18 &lt; 0 &gt; C. MeOH / water (10 mL, 1: 1) was added dropwise and the organic solvent was removed in vacuo. To the aqueous solution was added 2 M aqueous HCl (20 mL) dropwise. The aqueous solution was extracted with EtOAc (2 x 30 mL) and the combined organic phases were washed with 5% aqueous NaHCO ₃ (30 mL) and water (30 mL). The organic phase was dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give (3?, 5?, 6?, 7?) -6-ethyl-3,7-dihydroxy-cholan-23-carboxy-24-oic acid dimethyl ester (90 mg, 45% .

^{1 H NMR (700 MHz, CDCl} 3): δ = 3.75 (3H, s), 3.72 (3H, s), 3.48 (1H, dd, J = 11.0, 4.0), 3.69 (1H, bs), 3.40 (1H m), 2.18 (1H, m), 1.97-1.93 (2H, m), 1.85-1.75 (4H, m), 1.73-1.57 (4H, m), 1.51-1.11 , td, J = 14.3, 3.4), 0.93 (3H, d, J = 6.5), 0.90 (3H, t, J = 7.3), 0.64 (3H, s); ^{13 C NMR (176 MHz, CDCl} 3): δ = 170.5, 170.1, 72.3, 70.9, 56.3, 52.6, 52.4, 50.5, 49.4, 45.2, 42.8, 41.2, 40.0, 39.6, 35.6, 35.5, 35.2, 34.4, 34.0 , 33.2, 30.6, 28.2, 23.7, 23.2, 22.2, 20.7, 18.2, 11.8, 11.7.

Example  57 - ( 3α , 5β , 6α , 7α ) -6-ethyl-3,7- Dihydroxy -Cholan-23-carboxy-24-oic acid.

To a solution of (3α, 5β, 6α, 7α) -6-ethyl-3,7-dihydroxy-cholan-23-carboxy-24-oic acid dimethyl ester (70 mg) in IPA (2 mL, 28 vol) M aqueous NaOH (2 mL, 28 vol) was added and the mixture was stirred at 60 &lt; 0 &gt; C for 2 h. The organic solvent was removed in vacuo and the aqueous solution was adjusted to pH 1 with 2 M aqueous H ₂ SO ₄ . EtOAc (20 mL) was added and the mixture was stirred for 5 min. The aqueous phase was re-extracted with EtOAc (10 mL). The combined organic phases were washed with 5% aqueous NaCl (2 x 10 mL), dried over Na ₂ SO ₄ and was filtered and concentrated in vacuo (3α, 5β, 6α, 7α ) -6- ethyl-3,7-di Hydroxy-cholan-23-carboxy-24-oic acid as a white solid (54 mg, 81%).

^{1 H NMR (700 MHz, d} -6 acetone): δ = 3.58 (1H, bs), 3.32 (1H, dd, J = 11.1, 3.6), 3.18 (1H, m), 2.03 (1H, m), 1.90 (3H, m), 0.98 (3H, m), 0.87 (1 H, m), 1.48 (3H, d, J = 6.1), 0.85 (1H, m) 0.79 (3H, s), 0.75 (3H, t, J = 7.3), 0.74 (3H, s); ¹³ C NMR (176 MHz, d -6 acetone):? = 171.7, 171.3, 72.5, 70.4, 57.5, 51.4, 46.7, 43.4, 42.6, 41.3, 40.7, 36.7, 36.3, 36.2, 35.3, 34.6, , 30.6, 29.0, 24.3, 23.7, 23.2, 21.6, 18.7, 12.3, 12.1.

Example  58 - ( 3α , 5β , 6α , 7α ) -6-ethyl-3,7- Dihydroxy -Cholan-24-oic acid (OCA).

(25 mg) was added to a mixture of xylene (1.25 mL, 50 vol) and pyridine (250 [mu] L , 10 vol) and the solution was heated to reflux for 90 min. The cooled solution was diluted with EtOAc (20 mL) and washed with 1 M aqueous HCl (3 x 10 mL). The organic phase was washed with water (3 x 10 mL), 5 % aqueous NaCl (10 mL), dried over Na ₂ SO _4, filtered and concentrated. The residue was purified by column chromatography to give (3?, 5?, 6?, 7?) -6-ethyl-3,7-dihydroxy-cholan-24-o-acid as a white solid (19 mg, 82%).

¹ H and ¹³ C NMR were consistent with the reference samples of (3?, 5?, 6?, 7?) - 6-ethyl-3,7-dihydroxy-cholan-24-oic acid.

Claims (34)

Compounds of general formula (Ia) or salts or isotopic variations thereof:

(Ia)
In this formula,
R ² is H, halo, OH, or a protected OH group;
Y is a bond or a C _1-20 alkylene, C _2-20 alkenylene or C _2-20 alkynylene linker group, any of which is optionally substituted by one or more R ³ ;
Wherein each R ³ is independently H, halo, OH, protected OH group, or NR ⁸ R ⁹ ;
Wherein each R ⁸ and R ⁹ is independently H, C _1-6 alkyl, C (O) Ph, benzyl, phthalimide, tert -butyloxycarbonyl, or carboxybenzyl;
R ⁴ is ^{C (O) OR 10, OC} (O) R 10, C (O) NR 10 R 11, OR 10, OSi (R 13) 3, S (O) R 10, SO 2 R 10, OSO 2 _{^{R 10, SO 3 R 10,}} OSO 3 R 10, halo, CN, C (O) R 10, NR 10 R 11, BR 10 R 11, C (O) CH 2 N 2, -CH = CH 2, - C≡CH, CH [C (O) OR 10] 2, CH (BR 10 R 11) 2, ^{_{azide, NO 2, NR 10 C (}} O) NR 10 SO 2 R 11, NR 10 C (O) NR _{^{10 SO 2 NR 10 R 11,}} NR 10 SO 2 R 11, C (O) NR 10 SO 2 R 11, CH (XR 10) (XR 11), CH (R 10) (XR 11), phthalimide, Or a carboxylic acid analogue such as a tetrazole;
Wherein each X is independently O, S, or NR ⁸ ;
Wherein each R &lt; ¹⁰ &gt; and R &lt; ¹¹ &gt;
a. Hydrogen;
b. C _1-6 alkyl, C _1-20 alkyl, C _3-7 cycloalkyl, C _2-20 alkenyl, or C _2-20 alkynyl,
C _1-4 alkyl, C _1-4 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, OSO _{^{2 R 19, SO 3 R 19}} , OSO 3 R 19, N (R 19) 2, and 6-to 14-membered aryl or 5- to 14-membered heteroaryl group (each of which C _1-6 alkyl, C thereof _1-6 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO 3 R 19, and N ( R &lt; ¹⁹ &gt;)₂; or a pharmaceutically acceptable salt thereof;
c. 6- to 14-membered aryl, 5- to 14-membered heteroaryl group, or 3- to 10-membered heterocyclic ring, any of which is
(O) C _1-4 alkyl, SR ¹⁹ , C (O) C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, halo, NO ₂ , CN, OR ¹⁹ , ^{) OR 19, C (O)} N (R 19) 2, SO 2 R 19, SO 3 R 19, N (R 19) 2, Phenyl, 5- to 14-membered heteroaryl, 3- to 10-membered heterocyclic ring, methylenedioxy, and ethylene dioxy;
d. A polyethylene glycol residue;
e. R ⁴ is ^{C (O) NR 10 R 11} , CH (XR 10) (XR 11), CH (R 10) (XR 11), NR 10 R 11, BR 10 R 11, CH [C (O) OR 10 ] ₂ , or CH (BR ¹⁰ R ¹¹ ) ₂ , the R ¹⁰ and R ¹¹ groups may be combined with the atoms or atoms to which they are attached to form a 3- to 10-membered heterocyclic ring;
Wherein each R &lt; ¹⁹ &gt; is independently
H, C _1-6 alkyl, C _1-6 haloalkyl, or a 6- to 14-membered aryl or 5- to 14-membered heteroaryl group, each of which is halo, C _1-6 alkyl, and C _{1- 6} haloalkyl; &lt; / RTI &gt;
Wherein each R &lt; ¹³ &gt; is independently
a. C _1-20 alkyl, C _2-20 alkenyl or C _2-20 alkynyl, any of which is
^{_{Halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO 3 R 19, OSO 3 R 19, N (R 19 ) _2, and 6-to 14-membered aryl or 5- to 14-membered heteroaryl group (each of which C _1-6 alkyl, C _1-6 haloalkyl, halo, NO _2, CN, oR ^19, SO ₂ Optionally substituted by one or more substituents selected from R ¹⁹ , SO ₃ R ¹⁹ , and N (R ¹⁹ ) ₂ ;
b. 6- to 14-membered aryl or 5- to 14-membered heteroaryl group,
C _1-6 alkyl, C _1-6 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO ₃ R ^19, and N (R ¹⁹⁾ _2, and optionally substituted by one or more substituents selected from;
Wherein each R &lt; ¹⁹ &gt; is independently
H, Ci- ₆ alkyl, or Ci- ₆ haloalkyl;
Y and R ⁴ together form a group = CH _2;
R ⁵ is H, OH, or a protected OH group. The method according to claim 1,
Compounds of general formula (I) or salts or isotopic variations thereof:

(I)
In this formula,
R ² is H, halo, OH, or a protected OH group;
Y is a bond or a C _1-20 alkylene, C _2-20 alkenylene or C _2-20 alkynylene linker group, any of which is optionally substituted by one or more R ³ ;
Wherein each R ³ is independently halo, OR ⁸ , or NR ⁸ R ⁹ ;
Wherein each R ⁸ and R ⁹ is independently H or C _1-4 alkyl;
R ⁴ is ^{C (O) OR 10, OC} (O) R 10, C (O) NR 10 R 11, OR 10, OSi (R 13) 3, S (O) R 10, SO 2 R 10, OSO 2 _{^{R 10, SO 3 R 10,}} OSO 3 R 10, halo, CN, C (O) R 10, CH (OR 10) (OR 11), CH (R 10) (OR 11), CH (SR 10) ( ^{SR 11), NR 10 R 11} , BR 10 R 11, C (O) CH 2 N 2, -CH = CH 2, -C≡CH, CH [C (O) OR 10] 2, CH (BR 10 R ¹¹ ) ₂ , an azide, or a carboxylic acid mimetic group, such as a tetrazole;
Wherein each R &lt; ¹⁰ &gt; and R &lt; ¹¹ &gt;
a. Hydrogen;
b. C _1-20 alkyl, C _2-20 alkenyl or C _2-20 alkynyl, any of which is
^{_{Halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO 3 R 19, OSO 3 R 19, N (R 19 ) _2, and 6-to 14-membered aryl or 5- to 14-membered heteroaryl group (each of which C _1-6 alkyl, C _1-6 haloalkyl, halo, NO _2, CN, oR ^19, SR ¹⁹ selected ^{from, C (O) OR 19,} C (O) N (R 19) 2, SO 2 R 19, SO 3 R 19, and N (R ^19), optionally substituted by one or more substituents selected from ₂₎ Lt; / RTI &gt; is optionally substituted by one or more substituents;
c. 6- to 14-membered aryl or 5- to 14-membered heteroaryl group,
C _1-6 alkyl, C _1-6 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO ₃ R ^19, and N (R ¹⁹⁾ ₂ with one or more substituents selected from optionally substituted;
d. A polyethylene glycol residue;
e. R ⁴ is ^{C (O) NR 10 R 11} , CH (OR 10) (OR 11), CH (R 10) (OR 11), CH (SR 10) (SR 11), NR 10 R 11, BR 10 R ^{11, CH [C (O)} oR 10] 2, or CH (BR ¹⁰ R ¹¹⁾ ₂ in the case of R ¹⁰ and R ¹¹ group is combined with the atom or atoms to which they are attached, a 3- to 10-membered heteroaryl To form a cyclic ring;
Wherein each R &lt; ¹⁹ &gt; is independently
H, C _1-6 alkyl, C _1-6 haloalkyl, or a 6- to 14-membered aryl or 5- to 14-membered heteroaryl group, each of which is halo, C _1-6 alkyl, and C _{1- 6} haloalkyl; &lt; / RTI &gt;
Wherein each R &lt; ¹³ &gt; is independently
a. C _1-20 alkyl, C _2-20 alkenyl or C _2-20 alkynyl, any of which is
^{_{Halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO 3 R 19, OSO 3 R 19, N (R 19 ) _2, and 6-to 14-membered aryl or 5- to 14-membered heteroaryl group (each of which C _1-6 alkyl, C _1-6 haloalkyl, halo, NO _2, CN, oR ^19, SO ₂ Optionally substituted by one or more substituents selected from R ¹⁹ , SO ₃ R ¹⁹ , and N (R ¹⁹ ) ₂ ;
b. 6- to 14-membered aryl or 5- to 14-membered heteroaryl group,
C _1-6 alkyl, C _1-6 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO ₃ R ^19, and N (R ¹⁹⁾ _2, and optionally substituted by one or more substituents selected from;
Wherein each R &lt; ¹⁹ &gt; is independently
H, Ci- ₆ alkyl, or Ci- ₆ haloalkyl;
Y and R ⁴ together form a group = CH _2;
R ⁵ is H, OH, or a protected OH group. 3. The method according to claim 1 or 2,
R &lt; ² &gt; is H. 4. The method according to any one of claims 1 to 3,
Y is a bond or a C _1-3 alkylene or C _2-3 alkenylene linker group, each of which is optionally substituted by one or two R ³ groups, wherein R ³ is as defined in claim 1 or 2 &Lt; / RTI &gt; 5. The method of claim 4,
The compound or -CH = CH- - Y is -CH ₂ CH _2. 6. The method according to any one of claims 1 to 5,
R ³ is H, halo, OH, OC (O) R ¹⁴ , OSi (R ¹⁶ ) ₃ , or NR ⁸ R ⁹ ; Wherein R ¹⁴ is C _1-6 alkyl or phenyl; Each R ¹⁶ is independently C _1-6 alkyl or phenyl; Each R ⁸ and R ⁹ is independently H, methyl, ethyl or tert -butoxycarbonyl. 7. The method according to any one of claims 1 to 6,
R ⁴ is C (O) OR ¹⁰ , OR ¹⁰ , C (O) NR ¹⁰ R ¹¹ , SO ₃ R ¹⁰ , or OSO ₃ R ¹⁰ . 7. The method according to any one of claims 1 to 6,
R ⁴ is halo, CN, C (O) R 10, CH (XR 10) (XR 11), CH = CH 2, -C≡CH, CH [C (O) OR 10] 2, BR 10 R 11 or , Y and R ⁴ are a group = CH ₂ with a compound to form. 9. The method of claim 8,
R ⁴ is halo, CN, C (O) R 10, CH (OR 10) (OR 11), CH = CH 2, -C≡CH, CH [C (O) OR 10] 2, BR 10 R 11 or , Y and R ⁴ are a group = CH ₂ with a compound to form. 10. The method of claim 9,
R ⁴ is ^{C (O) OR 10, CONR} 10 R 11, OSO 2 R 10, OSO 3 R 10, CN, ^{azide, OR 10, OSi (R 13} ) 3, CH [(C (O) OR 10) ] ₂ , CH (OR ¹⁰ ) (OR ¹¹ ), NR ¹⁰ CONR ¹⁰ SO ₂ R ^11, and NR ¹⁰ SO ₂ R ¹¹ and tetrazole. 7. The method according to any one of claims 1 to 6,
R ⁴ is ^{C (O) OR 10, OC} (O) R 10, OR 10, OSi (R 13) 3, OSO 2 R 10, halo, CN, C (O) R 10, NR 10 R 11, CH [ C (O) OR ¹⁰ ] ₂ , azide, C (O) NR ¹⁰ SO ₂ R ¹¹ CH (XR ¹⁰ ) (XR ¹¹ ); A phthalimide, a tetrazole, or a substituted tetrazole. 12. The method according to any one of claims 1 to 11,
Each R &lt; ¹⁰ &gt; and R &lt; ¹¹ &gt;
a. Hydrogen;
b. C _1-10 alkyl, C _2-10 alkenyl, or C _2-10 alkynyl, any of which is
C _1-4 alkyl, C _1-4 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, OSO _{^{2 R 19, SO 3 R 19}} , OSO 3 R 19, N (R 19) 2, and 6-to 14-membered aryl or 5- to 14-membered heteroaryl group (each of which C _1-6 alkyl, C thereof _1-6 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO 3 R 19, and N ( R &lt; ¹⁹ &gt;)₂; or a pharmaceutically acceptable salt thereof;
c. 6- to 10-membered aryl or 5- to 10-membered heteroaryl group,
(O) C _1-4 alkyl, SR ¹⁹ , C (O) C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, halo, NO ₂ , CN, OR ¹⁹ , ^{) OR 19, C (O)} N (R 19) 2, SO 2 R 19, SO 3 R 19, N (R 19) 2, Phenyl, 5- to 14-membered heteroaryl, 3- to 10-membered heterocyclic ring, methylenedioxy, and ethylene dioxy;
d. A polyethylene glycol residue;
e. When R ⁴ is C (O) NR ¹⁰ R ¹¹ , CH (XR ¹⁰ ) (XR ¹¹ ), CH (R ¹⁰ ) (XR ¹¹ ), NR ¹⁰ R ¹¹ or BR ¹⁰ R ¹¹ , R ¹⁰ and R ¹¹ Group is taken together with the atoms or atoms to which they are attached to form a 3- to 10-membered heterocyclic ring. 12. The method according to any one of claims 1 to 11,
Each R &lt; ¹⁰ &gt; and R &lt; ¹¹ &gt;
a. Hydrogen;
b. C (O) OR ¹⁹ , C (O) C _1-6 alkyl, C _2-10 alkenyl, or C _2-10 alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO ₂ , CN, OR ¹⁹ , SR ¹⁹ , _{^{) N (R 19) 2,}} SO 2 R 19, SO 3 R 19, OSO 3 R 19, N (R 19) 2, and 6-to 14-membered aryl or 5- to 14-membered heteroaryl group (these each is C _1-6 alkyl, C _1-6 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19 , SO ₃ R ¹⁹ , and N (R ¹⁹ ) ₂ ; or a pharmaceutically acceptable salt thereof;
c. 6- to 10-membered aryl or 5- to 10-membered heteroaryl group,
C _1-6 alkyl, C _1-6 haloalkyl, ^{_{halo, NO 2, CN, OR 19}} , SR 19, C (O) OR 19, C (O) N (R 19) 2, SO 2 R 19, SO ₃ R ^19, and N (R ¹⁹⁾ ₂ with one or more substituents selected from optionally substituted;
d. A polyethylene glycol residue;
e. R ⁴ is ^{C (O) NR 10 R 11} , CH (OR 10) (OR 11), CH (R 10) (OR 11), CH (SR 10) (SR 11), NR 10 R 11, or BR ¹⁰ R ¹¹ in the case, R ¹⁰ and R ¹¹ group is combined with the atom or atoms to which they are attached, a 3- to 10-membered compounds that can form a heterocyclic ring. 14. The method according to any one of claims 1 to 13,
R ¹⁰ is hydrogen; Or C _1-6 , such as C _1-3 alkyl or C _2-6 , such as C _2-3 alkenyl, each of which is optionally substituted with 6- to 14-membered aryl such as phenyl, especially C _1-6 alkyl or benzyl &Lt; / RTI &gt; 7. The method according to any one of claims 1 to 6,
R ⁴ is C (O) OR ¹⁰ , OR ¹⁰ , SO ₃ R ¹⁰ , OSO ₃ R ¹⁰ , Halo, CN, C (O) R ¹⁰ , CH (XR ¹⁰ ) (XR ¹¹ ), CH [C (O) OR ¹⁰ ] ₂ , or BR ¹⁰ R ¹¹ ; Each R ¹⁰ and R ¹¹ is independently H, C _1-6 alkyl, or benzyl;
When R ⁴ is CH (OR ¹⁰ ) (OR ¹¹ ) or BR ¹⁰ R ¹¹ , R ¹⁰ and R ¹¹ combine with the atoms or atoms to which they are attached to form a 3- to 10-membered heterocyclic ring Or;
R ⁴ is C (O) NR ¹⁰ R ¹¹ substituted by C (O) OR ¹⁹ , OR ¹⁹ , SO ₃ R ¹⁹ , or OSO ₃ R ¹⁹ , and R ¹⁹ is H. 16. The method of claim 15,
&Lt; / RTI &gt; 17. The method according to any one of claims 1 to 16,
R &lt; ⁵ &gt; is H. Process for the preparation of a compound of formula (Ia) according to any one of claims 1 to 17, comprising reacting a compound of formula (IIa) with a halogenating agent followed by reaction with a base:

(IIa) (Ia)
Wherein Y, R ² , R ⁴ , and R ⁵ are as defined in any one of claims 1 to 17. 19. The method of claim 18,
The halogenating agent may be selected from the group consisting of Br ₂ , Cl ₂ , I ₂ , N -bromosuccinimide (NBS), N -chlorosuccinimide (NCS), N -iodosuccinimide (NIS), chloramine- ), tert -butyl hypochlorite, trichloroisocyanuric acid (TCCA), tribromoisocyanuric acid (TBCA), triiodoisocyanuric acid (TICA), 1,3-dichloro-5,5- hydantoin (DCDMH), 1,3- dibromo-5,5-dimethylhydantoin (DBDMH), 1,3- di-iodo-5,5-dimethylhydantoin (DIDMH), di with TiCl ₄ - tert -Butyl peroxide; Ca (OCl) ₂ with NaCl in AcOH; Or TMSCl with H ₂ O ₂ . 20. The method of claim 19,
The halogenating agent is selected from the group consisting of trichloroisocyanuric acid (TCCA), tribromoisocyanuric acid (TBCA), triiodoisocyanuric acid (TICA), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) Dibromo-5,5-dimethylhydantoin (DBDMH), or 1,3-diiodo-5,5-dimethylhydantoin (DIDMH). 20. The method of claim 19,
Wherein the halogenating agent is trichloroisocyanuric acid (TCCA) or tert -butyl hypochlorite. 22. The method according to any one of claims 19 to 21,
Wherein the halogenating agent is trichloroisocyanuric acid (TCCA). 23. The method according to any one of claims 19 to 22,
Wherein the reaction is carried out in a solvent selected from acetone, DMF, MeCN, or CH ₂ Cl ₂ , THF, t -butyl alcohol, acetic acid, dioxane, DMSO, formic acid, and water and mixtures thereof. 24. The method of claim 23,
Wherein the reaction is carried out in a solvent selected from acetone, water, formic acid, acetic acid, and mixtures thereof. A compound of formula (IIIxa) or a salt or isotopic variation thereof; Or a compound of formula (IIIya) or a salt or isotopic variation thereof:

(IIIxa)
Wherein X is Cl, Br, or I;
Wherein Y, R ² , R ⁴ and R ⁵ are as defined in any one of claims 1 to 17,

(IIIya)
Wherein X is Cl, Br, or I;
Wherein Y, R ² , R ⁴ , and R ⁵ are as defined in any one of claims 1 to 17. A mixture comprising a compound of formula (IIIxa) as defined in claim 25 and a compound of formula (IIIya). A process for preparing a compound of formula (Xa) or a salt or isotopic variant thereof, comprising the steps of:

(Xa)
(Wherein,
R ¹ is C _1-4 alkyl, C _2-4 alkenyl, or C _2-4 alkynyl optionally substituted by one or more substituents selected from halo, OR ⁶ , and NR ⁶ R ⁷ ;
Wherein each R ⁶ and R ⁷ is independently H or C _1-4 alkyl;
R ² is H, halo, or OH;
R &lt; ^5a &gt; is H or OH;
Y ¹ is a bond or a C _1-20 alkylene linker group optionally substituted by one or more R ³ ;
Y ¹ and R ⁴ together form a = CH ₂ group;
Wherein R ³ and R ⁴ are as defined in any one of claims 1 to 17,
(a) optionally alkylating the compound of formula (Ia) with an organometallic reagent to provide a compound of formula (IVa)

(IVa)
Wherein R &lt; ¹ &gt; is as defined for a compound of formula (Xa);
Y, R ² , R ⁴ , and R ⁵ are as defined in claim 1;
(b) reducing the compound of formula (IVa) using a suitable reducing agent to provide a compound of formula (Va)

(Va)
Wherein Y ¹ and R ¹ are as defined for a compound of formula (Xa);
R ² , R ⁴ , and R ⁵ are as defined in claim 1;
(c) oxidizing a compound of formula (Va) using a suitable oxidizing agent to provide a compound of formula (VIa):

(VIa)
Wherein Y ¹ and R ¹ are as defined for a compound of formula (Xa);
R ² , R ⁴ , and R ⁵ are as defined in claim 1;
(d) reducing the compound of formula (VIa) using a suitable reducing agent and removing the protecting group (s) when R ² and / or R ⁵ is protected OH, Wherein removal of the protecting group may take place before or after reduction. 28. The method of claim 27,
Compounds of formula (Ia), (IVa), (Va), (VIa) and (Xa) may be reacted with other compounds of formula (Ia), (IVa), (Va), (VIa) Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt; 29. The method of claim 28,
Any step can be carried out by reacting side chains of compounds of general formula (Ia), (IVa), (Va), (VIa), and (Xa) to compounds with alternative Y / Y ¹ and / or R ⁴ moieties The process consisting of reaching. Compounds of general formula (IVa) or salts or isotopic variations thereof:

(IVa)
Wherein R ¹ is C _1-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl optionally substituted by one or more substituents selected from halo, OR ⁶ and NR ⁶ R ⁷ ;
Wherein each R ⁶ and R ⁷ is independently H or C _1-4 alkyl;
Wherein Y, R ² , R ⁴ and R ⁵ are as defined in any one of claims 1 to 17. Compounds of general formula (Va) or salts or isotopic variations thereof:

(Va)
In this formula,
R ¹ is C _1-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl optionally substituted by one or more substituents selected from halo, OR ⁶ and NR ⁶ R ⁷ ;
Wherein each R ⁶ and R ⁷ is independently H or C _1-4 alkyl;
Y ¹ is a bond or a C _1-20 alkylene linker group optionally substituted by one or more R ³ ;
Y ¹ and R ⁴ together form a = CH ₂ group;
Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined in any one of claims 1 to 17. Compounds of general formula (IIIxz) or salts or isotopic variations thereof:

(IIIxz)
Wherein X is Cl, Br, or I;
R ⁴⁰ is C (O) H, C (O) C _1-4 alkyl, C (O) phenyl, C (O) benzyl, phenyl, benzyl, C _2-4 alkene or SO ₂ CF ₃ ; Here, in C (O) -phenyl, C (O) benzyl, phenyl, and benzyl is C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI &gt; is optionally substituted by one or more substituents selected;
Wherein Y, R ² , R ⁴ , and R ⁵ are as defined in any one of claims 1 to 17. A compound of the general formula (IIIyz) or a salt or isotope variant thereof:

(IIIyz)
Wherein X is Cl, Br, or I;
R ⁴⁰ is C (O) H, C (O) C _1-4 alkyl, C (O) phenyl, C (O) benzyl, phenyl, benzyl, C _2-4 alkenyl or SO ₂ CF ₃ ; Here, in C (O) -phenyl, C (O) benzyl, phenyl, and benzyl is C _1-4 alkyl, OC _1-4 alkyl, halo, nitro, C _1-4 haloalkyl, and OC _1-4 haloalkyl Lt; / RTI &gt; is optionally substituted by one or more substituents selected;
Wherein Y, R ² , R ⁴ , and R ⁵ are as defined in any one of claims 1 to 17. A compound of formula (Ia) or (I) or a salt or isotopic variant thereof selected from:
(6β, 7β, 22E) -6,7-epoxy-3-oxo-4,22-colladiene-24-oic acid ethyl ester (Example 1);
(6β, 7β, 20S) -6,7-epoxy-3-oxo-4,22-colladiene-24-oic acid ethyl ester (Example 5);
(6β, 7β, 20S) -6,7-epoxy-20-hydroxymethyl-pregna-4-en-3-one (Example 41);
(6β, 7β, 20S) -6,7-epoxy-20-bromomethyl-pregna-4-en-3-one (Example 42);
(20S) -methanesulfonyloxymethyl-6,7- [beta] -epoxy-4-prenenen-3-one (Example 43);
(20R) -cyanomethyl-6,7- [beta] -epoxy-4-prenenen-3-one (example 44);
(20S) -20-acetoxymethyl-6,7- [beta] -epoxy-pregna-4-en-3-one (example 45);
(6β, 7β, 20S) -6,7-epoxy-20- tert -butyldiphenylsiloxymethyl-pregna-4-en-3-one (Example 46);
(6β, 7β, 20S) -6,7-epoxy-20-azidomethyl-pregna-4-en-3-one (example 47);
(6β, 7β, 20S) -6,7-epoxy-20- ( N -phthalimidomethyl) -pregna-4,6-dien-3-one (example 48);
(6β, 7β, 20S) -6,7-epoxy-20-formyl-pregna-4-en-3-one (example 49);
(6β, 7β, 20S) -6,7-epoxy-20- (ethylene dioxymethyl) -pregna-4-en-3-one (Example 50); And
(6β, 7β) -6,7-epoxy-3-oxo-4-cholene-23-carboxy-24-oic acid dimethyl ester (example 51).

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